Immunology and Microbiology › Immunology

Immune cells in cancer

Works Count: 38127

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This cluster of papers explores the diverse aspects of macrophage activation and polarization, including their role in tumor microenvironments, interaction with myeloid-derived suppressor cells, modulation of immune responses, and metabolic regulation. The papers cover topics such as monocyte and macrophage heterogeneity, tissue-resident macrophages, and the impact of macrophage plasticity on health and disease.

Keywords

Macrophage; Activation; Polarization; Tumor-associated; Monocytes; Myeloid-derived suppressor cells; Inflammation; Metabolism; Cancer; Immunity

Tumour-educated macrophages promote tumour progression and metastasis

2004-01-01

Jeffrey W. Pollard

Macrophage plasticity and polarization in tissue repair and remodelling

2012-10-24

Alberto Mantovani , Subhra K. Biswas , Maria Rosaria Galdiero +2 more

Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2-like … Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2-like activation mode. Macrophages are credited with an essential role in remodelling during ontogenesis. In extraembryonic life, under homeostatic conditions, the macrophage trophic and remodelling functions are recapitulated in tissues such as bone, mammary gland, decidua and placenta. In pathology, macrophages are key components of tissue repair and remodelling that occur during wound healing, allergy, parasite infection and cancer. Interaction with cells bearing stem or progenitor cell properties is likely an important component of the role of macrophages in repair and remodelling. These properties of cells of the monocyte-macrophage lineage may represent a tool and a target for therapeutic exploitation.

Transcriptional Profiling of the Human Monocyte-to-Macrophage Differentiation and Polarization: New Molecules and Patterns of Gene Expression

2006-11-15

Fernando O. Martínez , Siamon Gordon , Massimo Locati +1 more

Abstract Comprehensive analysis of the gene expression profiles associated with human monocyte-to-macrophage differentiation and polarization toward M1 or M2 phenotypes led to the following main results: 1) M-CSF-driven monocyte-to-macrophage differentiation … Abstract Comprehensive analysis of the gene expression profiles associated with human monocyte-to-macrophage differentiation and polarization toward M1 or M2 phenotypes led to the following main results: 1) M-CSF-driven monocyte-to-macrophage differentiation is associated with activation of cell cycle genes, substantiating the underestimated proliferation potential of monocytes. 2) M-CSF leads to expression of a substantial part of the M2 transcriptome, suggesting that under homeostatic conditions a default shift toward M2 occurs. 3) Modulation of genes involved in metabolic activities is a prominent feature of macrophage differentiation and polarization. 4) Lipid metabolism is a main category of modulated transcripts, with expected up-regulation of cyclo-oxygenase 2 in M1 cells and unexpected cyclo-oxygenase 1 up-regulation in M2 cells. 5) Each step is characterized by a different repertoire of G protein-coupled receptors, with five nucleotide receptors as novel M2-associated genes. 6) The chemokinome of polarized macrophages is profoundly diverse and new differentially expressed chemokines are reported. Thus, transcriptome profiling reveals novel molecules and signatures associated with human monocyte-to-macrophage differentiation and polarized activation which may represent candidate targets in pathophysiology.

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The cost of dichotomising continuous variables

2006-05-04

Douglas G. Altman , Patrick Royston

<h3>ABSTRACT</h3> Myeloid-derived suppressor cells (MDSCs) are present in elevated numbers in TB patients and have been found to be permissive for <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) proliferation. To determine whether depletion of … <h3>ABSTRACT</h3> Myeloid-derived suppressor cells (MDSCs) are present in elevated numbers in TB patients and have been found to be permissive for <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) proliferation. To determine whether depletion of MDSCs may improve host control of TB, we used a novel diphtheria toxin-based fusion protein known as DABIL-4 that targets and depletes IL-4-receptor positive cells. We show that DABIL-4 depletes both PMN-MDSCs and M-MDSC in the mouse TB model, and that it reduces the lung bacillary burden of <i>Mtb</i>. These results indicate that MDSC-depleting therapies targeting the IL4 receptor are beneficial in TB and offer an avenue towards host-directed TB therapy.

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Tumor-Associated Macrophages: From Mechanisms to Therapy

2014-07-01

Roy Noy , Jeffrey W. Pollard

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Tissue-Resident Macrophages Self-Maintain Locally throughout Adult Life with Minimal Contribution from Circulating Monocytes

2013-04-01

Daigo Hashimoto , Andrew Chow , Clara Noizat +7 more

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CSF-1R inhibition alters macrophage polarization and blocks glioma progression

2013-09-22

Stephanie M. Pyonteck , Leila Akkari , Alberto J. Schuhmacher +7 more

Protective and pathogenic functions of macrophage subsets

2011-10-14

Peter J. Murray , Thomas A. Wynn

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Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes

2002-10-21

Alberto Mantovani , Silvano Sozzani , Massimo Locati +2 more

Polarization of Tumor-Associated Neutrophil Phenotype by TGF-β: “N1” versus “N2” TAN

2009-09-01

Zvi G. Fridlender , Jing Sun , Samuel Kim +5 more

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Myeloid-derived suppressor cells as regulators of the immune system

2009-02-07

Dmitry I. Gabrilovich , Srinivas Nagaraj

Putting tumours in context

2001-10-01

Mina J. Bissell , Derek C. Radisky

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A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells

2012-03-23

Christian Schulz , Elisa Gomez Perdiguero , Laurent Chorro +7 more

Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by … Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86 , published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present.

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Monocyte and macrophage heterogeneity

2005-12-01

Siamon Gordon , Philip R. Taylor

Macrophage activation and polarization

2007-11-01

Fernando O. Martínez

Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized … Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.

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Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene

1984-10-01

Michael E. Greenberg , Edward B. Ziff

Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice

2014-01-01

Liufu Deng , Hua Liang , Byron Burnette +4 more

High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances tumor control both locally and distantly. Unfortunately, local relapses often occur following IR treatment, … High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances tumor control both locally and distantly. Unfortunately, local relapses often occur following IR treatment, indicating that IR-induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator programmed death-ligand 1 (PD-L1, also called B7-H1) can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. Here, we demonstrate that PD-L1 was upregulated in the tumor microenvironment after IR. Administration of anti-PD-L1 enhanced the efficacy of IR through a cytotoxic T cell-dependent mechanism. Concomitant with IR-mediated tumor regression, we observed that IR and anti-PD-L1 synergistically reduced the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which suppress T cells and alter the tumor immune microenvironment. Furthermore, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumors through the cytotoxic actions of TNF. Our data provide evidence for a close interaction between IR, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and radiotherapy.

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Exploring the full spectrum of macrophage activation

2008-11-25

David M. Mosser , Justin P. Edwards

Macrophage biology in development, homeostasis and disease

2013-04-01

Thomas A. Wynn , Ajay Chawla , Jeffrey W. Pollard

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Macrophage Diversity Enhances Tumor Progression and Metastasis

2010-04-01

Bin‐Zhi Qian , Jeffrey W. Pollard

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Coordinated regulation of myeloid cells by tumours

2012-03-22

Dmitry I. Gabrilovich , Suzanne Ostrand‐Rosenberg , Vincenzo Bronte

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Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm

2010-09-20

Subhra K. Biswas , Alberto Mantovani

Functional polarization of tumour-associated macrophages by tumour-derived lactic acid

2014-07-11

Oscar R. Colegio , Ngoc-Quynh Chu , Alison L. Szabo +7 more

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Alternative Activation of Macrophages: Mechanism and Functions

2010-05-01

Siamon Gordon , Fernando O. Martínez

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Macrophage plasticity and polarization: in vivo veritas

2012-03-01

Antonio Sica , Alberto Mantovani

Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which … Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.

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Macrophages: Obligate Partners for Tumor Cell Migration, Invasion, and Metastasis

2006-01-01

John S. Condeelis , Jeffrey W. Pollard

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Transcriptional regulation of macrophage polarization: enabling diversity with identity

2011-10-25

Toby Lawrence , Gioacchino Natoli

Monocyte recruitment during infection and inflammation

2011-10-10

Chao Shi , Eric G. Pamer

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Succinate is an inflammatory signal that induces IL-1β through HIF-1α

2013-03-22

Gillian M. Tannahill , Annie M. Curtis , Juraj Adamik +7 more

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The chemokine system in diverse forms of macrophage activation and polarization

2004-11-06

Alberto Mantovani , Antonello Sica , Silvano Sozzani +3 more

Immunity, Inflammation, and Cancer

2010-03-01

Sergei I. Grivennikov , Florian R. Greten , Michael Karin

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Tissue-Resident Macrophage Enhancer Landscapes Are Shaped by the Local Microenvironment

2014-12-01

Yonit Lavin , Deborah R. Winter , Ronnie Blecher‐Gonen +5 more

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The tumor microenvironment and its role in promoting tumor growth

2008-10-06

Theresa L. Whiteside

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Distinct Role of Macrophages in Different Tumor Microenvironments

2006-01-15

Claire E. Lewis , Jeffrey W. Pollard

Abstract Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with … Abstract Macrophages are prominent in the stromal compartment of virtually all types of malignancy. These highly versatile cells respond to the presence of stimuli in different parts of tumors with the release of a distinct repertoire of growth factors, cytokines, chemokines, and enzymes that regulate tumor growth, angiogenesis, invasion, and/or metastasis. The distinct microenvironments where tumor-associated macrophages (TAM) act include areas of invasion where TAMs promote cancer cell motility, stromal and perivascular areas where TAMs promote metastasis, and avascular and perinecrotic areas where hypoxic TAMs stimulate angiogenesis. This review will discuss the evidence for differential regulation of TAMs in these microenvironments and provide an overview of current attempts to target or use TAMs for therapeutic purposes. (Cancer Res 2006; 66(2): 605-12)

A cytokine-mediated link between innate immunity, inflammation, and cancer

2007-05-01

Wan‐Wan Lin , Michael Karin

It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment that is an indispensable participant in the neoplastic … It has been established that cancer can be promoted and/or exacerbated by inflammation and infections. Indeed, chronic inflammation orchestrates a tumor-supporting microenvironment that is an indispensable participant in the neoplastic process. The mechanisms that link infection, innate immunity, inflammation, and cancer are being unraveled at a fast pace. Important components in this linkage are the cytokines produced by activated innate immune cells that stimulate tumor growth and progression. In addition, soluble mediators produced by cancer cells recruit and activate inflammatory cells, which further stimulate tumor progression. However, inflammatory cells also produce cytokines that can limit tumor growth. Here we provide an overview of the current understanding of the role of inflammation-induced cytokines in tumor initiation, promotion, and progression.

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The M1 and M2 paradigm of macrophage activation: time for reassessment

2014-02-28

Fernando O. Martínez , Siamon Gordon

Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are … Macrophages are endowed with a variety of receptors for lineage-determining growth factors, T helper (Th) cell cytokines, and B cell, host, and microbial products. In tissues, macrophages mature and are activated in a dynamic response to combinations of these stimuli to acquire specialized functional phenotypes. As for the lymphocyte system, a dichotomy has been proposed for macrophage activation: classic vs. alternative, also M1 and M2, respectively. In view of recent research about macrophage functions and the increasing number of immune-relevant ligands, a revision of the model is needed. Here, we assess how cytokines and pathogen signals influence their functional phenotypes and the evidence for M1 and M2 functions and revisit a paradigm initially based on the role of a restricted set of selected ligands in the immune response.

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Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors

2014-12-02

Elisa Gomez Perdiguero , Kay Klapproth , Christian Schulz +7 more

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Obesity induces a phenotypic switch in adipose tissue macrophage polarization

2007-01-02

Carey N. Lumeng , Jennifer L. Bodzin , Alan R. Saltiel

Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that … Adipose tissue macrophages (ATMs) infiltrate adipose tissue during obesity and contribute to insulin resistance. We hypothesized that macrophages migrating to adipose tissue upon high-fat feeding may differ from those that reside there under normal diet conditions. To this end, we found a novel F4/80+CD11c+ population of ATMs in adipose tissue of obese mice that was not seen in lean mice. ATMs from lean mice expressed many genes characteristic of M2 or “alternatively activated” macrophages, including Ym1, arginase 1, and Il10. Diet-induced obesity decreased expression of these genes in ATMs while increasing expression of genes such as those encoding TNF-α and iNOS that are characteristic of M1 or “classically activated” macrophages. Interestingly, ATMs from obese C-C motif chemokine receptor 2–KO (Ccr2-KO) mice express M2 markers at levels similar to those from lean mice. The antiinflammatory cytokine IL-10, which was overexpressed in ATMs from lean mice, protected adipocytes from TNF-α–induced insulin resistance. Thus, diet-induced obesity leads to a shift in the activation state of ATMs from an M2-polarized state in lean animals that may protect adipocytes from inflammation to an M1 proinflammatory state that contributes to insulin resistance.

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The role of tumour‐associated macrophages in tumour progression: implications for new anticancer therapies

2002-01-22

Lynne Bingle , Nicola J. Brown , Claire E. Lewis

Abstract The role of macrophages in tumour growth and development is complex and multifaceted. Whilst there is limited evidence that tumour‐associated macrophages (TAMs) can be directly tumouricidal and stimulate the … Abstract The role of macrophages in tumour growth and development is complex and multifaceted. Whilst there is limited evidence that tumour‐associated macrophages (TAMs) can be directly tumouricidal and stimulate the anti‐tumour activity of T cells, there is now contrasting evidence that tumour cells are able to block or evade the activity of TAMs at the tumour site. In some cases, tumour‐derived molecules even redirect TAM activities to promote tumour survival and growth. Indeed, evidence has emerged for a symbiotic relationship between tumour cells and TAMs, in which tumour cells attract TAMs and sustain their survival, with TAMs then responding to micro‐environmental factors in tumours such as hypoxia (low oxygen tension) by producing important mitogens as well as various growth factors and enzymes that stimulate tumour angiogenesis. This review presents evidence for the number and/or distribution of TAMs being linked to prognosis in different types of human malignancy. It also outlines the range of pro‐ and anti‐tumour functions performed by TAMs, and the novel therapies recently devised using TAMs to stimulate host immune responses or deliver therapeutic gene constructs to solid tumours. Copyright © 2002 John Wiley & Sons, Ltd.

Fate Mapping Reveals Origins and Dynamics of Monocytes and Tissue Macrophages under Homeostasis

2012-12-27

Simon Yona , Ki-Wook Kim , Yochai Wolf +7 more

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Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines

2014-07-01

Peter J. Murray , Judith E. Allen , Subhra K. Biswas +7 more

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Transcriptome-Based Network Analysis Reveals a Spectrum Model of Human Macrophage Activation

2014-02-01

Jia Xue , Susanne V. Schmidt , Jil Sander +7 more

Highlights•Macrophages react with specific transcriptional programming upon distinct signals•Activation by TNF, PGE2, and P3C activates a STAT4-associated transcriptional program•NFKB1, JUNB, and CREB1 are central transcription factors of macrophage activation•Inflammatory signatures … Highlights•Macrophages react with specific transcriptional programming upon distinct signals•Activation by TNF, PGE2, and P3C activates a STAT4-associated transcriptional program•NFKB1, JUNB, and CREB1 are central transcription factors of macrophage activation•Inflammatory signatures are lost in alveolar macrophages from COPD patientsSummaryMacrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease.Graphical abstract

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M-1/M-2 Macrophages and the Th1/Th2 Paradigm

2000-06-15

Charles D. Mills , Kristi Kincaid , Jennifer Alt +2 more

Abstract Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily … Abstract Evidence is provided that macrophages can make M-1 or M-2 responses. The concept of M-1/M-2 fomented from observations that macrophages from prototypical Th1 strains (C57BL/6, B10D2) are more easily activated to produce NO with either IFN-γ or LPS than macrophages from Th2 strains (BALB/c, DBA/2). In marked contrast, LPS stimulates Th2, but not Th1, macrophages to increase arginine metabolism to ornithine. Thus, M-1/M-2 does not simply describe activated or unactivated macrophages, but cells expressing distinct metabolic programs. Because NO inhibits cell division, while ornithine can stimulate cell division (via polyamines), these results also indicate that M-1 and M-2 responses can influence inflammatory reactions in opposite ways. Macrophage TGF-β1, which inhibits inducible NO synthase and stimulates arginase, appears to play an important role in regulating the balance between M-1 and M-2. M-1/M-2 phenotypes are independent of T or B lymphocytes because C57BL/6 and BALB/c NUDE or SCID macrophages also exhibit M-1/M-2. Indeed, M-1/M-2 proclivities are magnified in NUDE and SCID mice. Finally, C57BL/6 SCID macrophages cause CB6F1 lymphocytes to increase IFN-γ production, while BALB/c SCID macrophages increase TGF-β production. Together, the results indicate that M-1- or M-2-dominant macrophage responses can influence whether Th1/Th2 or other types of inflammatory responses occur.

A guide to immunometabolism for immunologists

2016-07-11

Luke O'neill , Rigel J. Kishton , Jeff Rathmell

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Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards

2016-07-06

Vincenzo Bronte , Sven Brandau , Shu‐Hsia Chen +7 more

Abstract Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to … Abstract Myeloid-derived suppressor cells (MDSCs) have emerged as major regulators of immune responses in cancer and other pathological conditions. In recent years, ample evidence supports key contributions of MDSC to tumour progression through both immune-mediated mechanisms and those not directly associated with immune suppression. MDSC are the subject of intensive research with >500 papers published in 2015 alone. However, the phenotypic, morphological and functional heterogeneity of these cells generates confusion in investigation and analysis of their roles in inflammatory responses. The purpose of this communication is to suggest characterization standards in the burgeoning field of MDSC research.

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Tumour-associated macrophages as treatment targets in oncology

2017-01-24

Alberto Mantovani , Federica Marchesi , Alberto Malesci +2 more

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Macrophage plasticity, polarization, and function in health and disease

2018-01-10

Abbas Shapouri Moghaddam , Saeed Mohammadian Haftcheshmeh , Hossein Vazini +7 more

Macrophages are heterogeneous and their phenotype and functions are regulated by the surrounding micro-environment. Macrophages commonly exist in two distinct subsets: 1) Classically activated or M1 macrophages, which are pro-inflammatory … Macrophages are heterogeneous and their phenotype and functions are regulated by the surrounding micro-environment. Macrophages commonly exist in two distinct subsets: 1) Classically activated or M1 macrophages, which are pro-inflammatory and polarized by lipopolysaccharide (LPS) either alone or in association with Th1 cytokines such as IFN-γ, GM-CSF, and produce pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-6, IL-12, IL-23, and TNF-α; and 2) Alternatively activated or M2 macrophages, which are anti-inflammatory and immunoregulatory and polarized by Th2 cytokines such as IL-4 and IL-13 and produce anti-inflammatory cytokines such as IL-10 and TGF-β. M1 and M2 macrophages have different functions and transcriptional profiles. They have unique abilities by destroying pathogens or repair the inflammation-associated injury. It is known that M1/M2 macrophage balance polarization governs the fate of an organ in inflammation or injury. When the infection or inflammation is severe enough to affect an organ, macrophages first exhibit the M1 phenotype to release TNF-α, IL-1β, IL-12, and IL-23 against the stimulus. But, if M1 phase continues, it can cause tissue damage. Therefore, M2 macrophages secrete high amounts of IL-10 and TGF-β to suppress the inflammation, contribute to tissue repair, remodeling, vasculogenesis, and retain homeostasis. In this review, we first discuss the basic biology of macrophages including origin, differentiation and activation, tissue distribution, plasticity and polarization, migration, antigen presentation capacity, cytokine and chemokine production, metabolism, and involvement of microRNAs in macrophage polarization and function. Secondly, we discuss the protective and pathogenic role of the macrophage subsets in normal and pathological pregnancy, anti-microbial defense, anti-tumor immunity, metabolic disease and obesity, asthma and allergy, atherosclerosis, fibrosis, wound healing, and autoimmunity.

Macrophages as regulators of tumour immunity and immunotherapy

2019-02-04

David G. DeNardo , Brian Ruffell

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The Tumor Microenvironment Innately Modulates Cancer Progression

2019-07-26

Dominique C. Hinshaw , Lalita A. Shevde

Cancer development and progression occurs in concert with alterations in the surrounding stroma. Cancer cells can functionally sculpt their microenvironment through the secretion of various cytokines, chemokines, and other factors. … Cancer development and progression occurs in concert with alterations in the surrounding stroma. Cancer cells can functionally sculpt their microenvironment through the secretion of various cytokines, chemokines, and other factors. This results in a reprogramming of the surrounding cells, enabling them to play a determinative role in tumor survival and progression. Immune cells are important constituents of the tumor stroma and critically take part in this process. Growing evidence suggests that the innate immune cells (macrophages, neutrophils, dendritic cells, innate lymphoid cells, myeloid-derived suppressor cells, and natural killer cells) as well as adaptive immune cells (T cells and B cells) contribute to tumor progression when present in the tumor microenvironment (TME). Cross-talk between cancer cells and the proximal immune cells ultimately results in an environment that fosters tumor growth and metastasis. Understanding the nature of this dialog will allow for improved therapeutics that simultaneously target multiple components of the TME, increasing the likelihood of favorable patient outcomes.

Macrophage Polarization

2016-11-04

Peter J. Murray

Macrophage polarization refers to how macrophages have been activated at a given point in space and time. Polarization is not fixed, as macrophages are sufficiently plastic to integrate multiple signals, … Macrophage polarization refers to how macrophages have been activated at a given point in space and time. Polarization is not fixed, as macrophages are sufficiently plastic to integrate multiple signals, such as those from microbes, damaged tissues, and the normal tissue environment. Three broad pathways control polarization: epigenetic and cell survival pathways that prolong or shorten macrophage development and viability, the tissue microenvironment, and extrinsic factors, such as microbial products and cytokines released in inflammation. A plethora of advances have provided a framework for rationally purifying, describing, and manipulating macrophage polarization. Here, I assess the current state of knowledge about macrophage polarization and enumerate the major questions about how activated macrophages regulate the physiology of normal and damaged tissues.

Specific inflammatory stimuli that engage innate immune sensors induce novel CD103 expression profiles in macrophages

2025-06-24

Nasry Zane Bouzeineddine , Sébastien Talbot , Sameh Basta +1 more | Frontiers in Cellular and Infection Microbiology

The integrin CD103 is an adhesion molecule that facilitates immune cell retention in epithelial tissues through its interaction with E-cadherin. It is a marker for certain CD8+ T-cell subpopulations and … The integrin CD103 is an adhesion molecule that facilitates immune cell retention in epithelial tissues through its interaction with E-cadherin. It is a marker for certain CD8+ T-cell subpopulations and conventional type 1 dendritic cells (cDC1), but its presence on macrophages remains poorly characterized. Macrophage differentiation is influenced by M-CSF and GM-CSF, and we investigated whether macrophages can also express CD103 under inflammatory conditions. We examined baseline CD103 expression in bone marrow-derived macrophages (BMDMs) differentiated in M-CSF or GM-CSF and then stimulated them with pathogen-associated molecular patterns (PAMPs) or examined them following viral infection. We found that CD103 is minimally expressed at baseline but is selectively upregulated in M-CSF-differentiated macrophages after stimulation with endosomal TLR agonists. Mechanistically, p38 MAPK inhibition prevented CD103 upregulation, suggesting that this process is mediated by p38 MAPK signaling. Furthermore, in vivo LCMV infection induced CD103 expression on peritoneal macrophages. These findings demonstrate that macrophages can express CD103 under specific inflammatory conditions, challenging the assumption that CD103 is restricted to T cells and dendritic cells. This study expands our understanding of CD103 beyond its recognized roles in T cells and DCs, providing new insight into its regulation by macrophages.

Enhanced Trained Immunity in Peripheral Monocytes in Unstable Angina With Elevated High-Sensitivity C-Reactive Protein

2025-06-24

Jiyu Zhang , Fen Yang , Y.P. Liao +7 more | JACC Basic to Translational Science

Myeloid-derived suppressor cells modulation in the context of tumor microenvironment for gastric cancer

2025-06-24

José Darío Portillo‐Miño , Jhon Jairo Calderón-Leytón , Erika Ruíz‐García +1 more | Clinical & Translational Oncology

Impact of M2 Macrophages on Tumor Growth and Progression in Tongue Squamous Cell Carcinoma

2025-06-24

Mimi Abo-Ayoub Ashqar | International Journal of Oral and Maxillofacial Surgery

H3K9 lactylation in malignant cells facilitates CD8+ T cell dysfunction and poor immunotherapy response

2025-06-24

Hong Ma | International Journal of Oral and Maxillofacial Surgery

Immunogenic cell death-related biomarkers in heart failure probed by transcriptome and single-cell sequencing

2025-06-24

Haoyue Wang , Dongdong Wu , Gangfei Han +6 more | Frontiers in Immunology

Background Heart failure (HF) represents the terminal stage of various cardiovascular disorders, with immunogenic cell death (ICD) potentially influencing HF progression through modulation of immune cell activity. This study aimed … Background Heart failure (HF) represents the terminal stage of various cardiovascular disorders, with immunogenic cell death (ICD) potentially influencing HF progression through modulation of immune cell activity. This study aimed to identify ICD-associated biomarkers in patients with HF and explore their underlying mechanisms. Methods Data from GSE57338, GSE3586 and GSE5406 were retrieved from the Gene Expression Omnibus (GEO) database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify candidate genes, followed by enrichment analysis and Protein-Protein Interaction (PPI) network construction. Candidate biomarkers were selected using two machine learning approaches and validated for expression levels, with receiver operating characteristic (ROC) curve analysis determining the final biomarkers. A nomogram model was built based on the biomarkers, followed by molecular regulatory network analysis, gene set enrichment analysis (GSEA), immune infiltration assessment, and drug prediction. Additionally, key cells were selected for pseudo-time and cell communication analysis using the GSE183852 dataset. Next, pseudotemporal analysis was also performed on key cell subpopulations. Real-time quantitative PCR (RT-qPCR) was employed to validate the biomarkers. Results Three biomarkers, CD163, FPR1, and VSIG4, were identified as having significant diagnostic value for HF. GSEA revealed their enrichment in ribosomal and immune cell-related pathways. These biomarkers were notably correlated with CD8 T cells and M2 macrophages. Carbachol and etynodiol were predicted to interact with all three biomarkers. Single-cell RNA sequencing identified nine cell types, with expression of the biomarkers confined to monocytes and macrophages. Strong cell communication was observed between these cell types and fibroblasts. Expression of CD163 and VSIG4 decreased over time in monocytes and macrophages, whereas FPR1 showed an upward trend. In addition, the expression levels of CD163 and VSIG4 increased in subpopulations of monocytes and macrophages, whereas FPR1 showed a decreasing trend. RT-qPCR results confirmed significant down-regulation of CD163, FPR1, and VSIG4 in patients with HF and animal models. Conclusions This study identified and validated three ICD-related biomarkers in HF—CD163, FPR1, and VSIG4—offering a novel theoretical foundation for the clinical diagnosis and treatment of HF.

Interactions between glioblastoma and myeloid cells

2025-06-24

Yuting Li , Yu‐Hong Chen , Kaiyong Cai +7 more | Frontiers in Cell and Developmental Biology

Standing as the most aggressive form of primary malignant tumor, Glioblastoma (GBM) tumors with marked heterogeneity represents one of the enormous challenges in glioma treatment. Myeloid cells, which includes neutrophils, … Standing as the most aggressive form of primary malignant tumor, Glioblastoma (GBM) tumors with marked heterogeneity represents one of the enormous challenges in glioma treatment. Myeloid cells, which includes neutrophils, myeloid-derived suppressor cells, microglia, and macrophages, play a pivotal role in the tumor microenvironment of GBM. In the tumor microenvironment (TME), T cells and natural killer (NK) cells exert anti-tumor functions, whereas myeloid-derived suppressor cells (MDSCs) can promote tumor progression by suppressing these immune responses. Therefore, MDSCs play a critical role in shaping the effectiveness of immunotherapy. TME has constrained the ability of traditional GBM treatment approaches to significantly enhance prognostic outcomes for patients. This category encompasses conventional therapies like surgical resection and radiation therapy, along with cutting-edge methodologies such as immunotherapy. Through extensive investigations into the dynamic interactions between the GBM microenvironment and neoplastic cells, both targeted treatment strategies and innovative immunotherapeutic modalities have emerged, offering promising new directions for clinical intervention. This review focuses on the interactions between GBM and myeloid cells (MCs), providing novel insights into the oncogenesis and progression of GBM.

CD18 and CD36 expression in neutrophils from tumors and tumor-draining lymph nodes: implications for metastasis in oral squamous cell carcinoma

2025-06-23

Sandra Ekstedt , Eduardo I. Cardenas , Krzysztof Piersiala +6 more | Clinical & Experimental Metastasis

Neutrophil infiltration in tumors and tumor-draining lymph nodes (TDLNs) influences oral squamous cell carcinoma (OSCC) progression and metastasis. Neutrophils can exhibit an immunosuppressive phenotype, with CD18 and CD36 potentially linked … Neutrophil infiltration in tumors and tumor-draining lymph nodes (TDLNs) influences oral squamous cell carcinoma (OSCC) progression and metastasis. Neutrophils can exhibit an immunosuppressive phenotype, with CD18 and CD36 potentially linked to this. This study characterizes CD18/CD36 expression on neutrophils from different OSCC microenvironments and their association with metastasis. We assessed CD18 and CD36 expression on neutrophils from OSCC tumors, TDLNs, and healthy lymph nodes using flow cytometry. We also examined whether co-culture with the CAL27 oral cancer cell line influenced CD18/CD36 expression in blood neutrophils from healthy donors. Neutrophils from OSCC tumors and TDLNs exhibited higher CD18 expression than those from healthy lymph nodes, while CD36 was increased only in OSCC tumors. The highest CD18/CD36 expression was observed in metastasis. In vitro co-culture with CAL27 cells prolonged neutrophil survival and enhanced CD18 expression but had no impact on CD36 levels. Increased CD18/CD36 expression in OSCC neutrophils, particularly in metastasis, suggests their role in tumorigenesis. The elevated CD18 expression in TDLNs highlights enhanced neutrophil-lymphocyte interactions during cancer progression. Our in vitro findings underscore the ability of cancer cells to modulate neutrophil lifespan and phenotype, though this may not fully replicate the tumor microenvironment. This study provides insight into neutrophil contributions to OSCC progression and supports their potential as therapeutic targets.

Identification of conserved and tissue-restricted transcriptional profiles for lipid associated macrophages

2025-06-23

Yingzheng Xu , Hannah Hillman , Michael Chang +4 more | Communications Biology

Macrophages are essential immune cells in all tissues and are vital for maintaining tissue homeostasis, immune surveillance, and immune responses. Considerable efforts have identified shared and tissue-specific gene programs for … Macrophages are essential immune cells in all tissues and are vital for maintaining tissue homeostasis, immune surveillance, and immune responses. Considerable efforts have identified shared and tissue-specific gene programs for macrophages across organs during homeostasis. This information has dramatically enhanced the understanding of tissue-restricted macrophage programming and function. However, few studies have addressed the overlapping and tissue-specific responses of macrophage subsets following inflammation. One subset of macrophages observed across several studies, lipid-associated macrophages (LAMs), have gained interest due to their unique role in lipid metabolism and potential as a therapeutic target. LAMs are associated with regulating disease outcomes in metabolically related disorders including atherosclerosis, obesity, and metabolic dysfunction-associated steatotic liver disease. We utilized single-cell RNA sequencing datasets to profile LAM diversity across multiple tissues and inflammatory conditions in mice and humans, to define a shared LAM transcriptional profile, including Trem2 and Lpl, and sets of tissue-specific gene programs. Importantly, LAM markers were highly conserved with human LAM populations that emerge in inflammation. Overall, this analysis provides a detailed transcriptional landscape of tissue-restricted and shared LAM gene programs, data that may help instruct appropriate molecular targets for broad or tissue-restricted therapeutic interventions to modulate LAM populations in disease.

CD16 and Siglec expression refine the phenotypic heterogeneity of steady-state myeloid-derived suppressor cells

2025-06-23

Chris D. St. Laurent , Zeinab Jame-Chenarboo , Alyssa Beck +4 more | Frontiers in Oncology

Background Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) mediate cancer immune suppression by promoting an immunosuppressive microenvironment that inhibits effective anti-tumor immunity. However, they are still a poorly understood, heterogeneous mix of … Background Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) mediate cancer immune suppression by promoting an immunosuppressive microenvironment that inhibits effective anti-tumor immunity. However, they are still a poorly understood, heterogeneous mix of neutrophil subsets. This study aims to determine the Siglec expression profile on several neutrophil subsets and assess their immunosuppressive ability. Methods We identified CD16 high and CD16 low neutrophil subsets from the low-density fractions of human peripheral blood and compared them to high-density neutrophils. We profiled the expression of the entire family of Siglecs on these three key neutrophil populations under steady-state conditions in healthy subjects as well as cancer patients. Moreover, the ability of these populations, isolated from healthy subjects, to suppress T cell proliferation was assessed. Results Two distinct subpopulations were investigated within the low-density fraction of human peripheral blood (CD15 + CD66b + CD16 low and CD15 + CD66b + CD16 high ) and compared to high-density neutrophils (CD15 + CD66b + CD16 high ). We found that in addition to CD33 (Siglec-3), Siglec-5/-14, -7, and -9, are differentially expressed on the CD16 low and CD16 high low-density subsets in both healthy, steady-state subjects, and cancer patients. Upregulated expression of CD33 on the CD16 low cells led to the initial speculation that they are MDSCs. As the differential expression of Siglec-9 between these two populations was striking, we used CD16 and Siglec-9 double staining to quantify these populations, which demonstrated that the CD16 low Siglec-9 low population is greatly upregulated in cancer patients. The CD16 high low-density and high-density neutrophils, but not the CD16 low low-density neutrophils from healthy subjects, inhibited T cell proliferation, indicating that the CD16 low Siglec-9 low population are not MDSCs. Conclusions These results demonstrate that Siglecs are differentially expressed on neutrophil subsets, and along with CD16, may be used to help further define what is a PMN-MDSC. Consistent with current observations by others, PMN-MDSCs may encompass an array of neutrophil subtypes, including low-density neutrophils, and point to the need for more work to precisely define the genetic signatures of PMN-MDSCs.

Bone marrow tumor microenvironment profiling predicts distinct immunosuppressive phenotypes and immunotherapy potential in AML patients

2025-06-23

Litiele Cezar da Cruz , Yejin Lee , Ji Yeon Paik +3 more | Biomedicine & Pharmacotherapy

Tumor-Associated Macrophage in Breast Tumor Microenvironment

2025-06-21

Ling Ma , Yuexinzi Jin , Jian Xu +1 more | International Journal of Molecular Sciences

Breast cancer (BC) is the most common cancer in women worldwide. It is one of the main causes of cancer-related mortality. The breast tumor microenvironment (Br-TME) has emerged as an … Breast cancer (BC) is the most common cancer in women worldwide. It is one of the main causes of cancer-related mortality. The breast tumor microenvironment (Br-TME) has emerged as an important factor related to BC development and prognosis. Tumor-associated macrophages (TAMs) are the main effector cells in the Br-TME; they play key roles in regulating angiogenesis, immunosuppression, metastasis, and chemoresistance in BC patients. In this review, we introduce the macrophage niche in the Br-TME, particularly emphasizing the origin of TAMs. Next, we summarize the typical pathways and molecular mechanisms of the interactions between TAMs and various other components in the Br-TME. Finally, we provide an overview of drugs that target TAMs and discuss the prevailing technologies for drug delivery in the context of BC treatment. Identification of the dynamic variations in tumor-promoting TAMs will help reveal the key links that drive BC progression. This review provides a theoretical basis for upcoming clinical trials that may substantially benefit patients.

Multimerin-1 modulates macrophage M2 polarization and enhances tumor cell stemness in glioblastoma

2025-06-21

Chao Huang , Xuebin Yu , Yong-Zhi Zhou +3 more | Neurological Research

Glioblastoma (GBM) is one of the most aggressive brain tumors, with a poor prognosis. Brain tumor stem cells (BTSCs) play a central role in GBM progression and recurrence. This study … Glioblastoma (GBM) is one of the most aggressive brain tumors, with a poor prognosis. Brain tumor stem cells (BTSCs) play a central role in GBM progression and recurrence. This study aimed to identify key BTSC-related genes associated with GBM prognosis and explore their potential biological functions. BTSC-related differentially expressed genes (DEGs) were identified by integrating gene expression data from public databases. Functional enrichment analyses were conducted to explore their biological relevance in GBM. The key variables associated with GBM risk and prognosis were selected using the machine learning method. Immune cell infiltration in GBM was explored through CIBERSORT. Finally, the effects of MMRN1 on cell stemness and macrophage polarization were investigated using in vitro experiments. A total of 26 upregulated BTSC-related DEGs in GBM were identified, which were enriched in immune response and pathways in cancer. MMRN1 and age were the key variables associated with GBM risk and prognosis. Higher MMRN1 expression and older age indicated a poor prognosis. MMRN1 expression was significantly elevated in GBM tissues, especially in BTSCs. Mechanistically, MMRN1 activated the TLR7/8/9-IRF5 signaling pathway and promoted M2 macrophage polarization. In vitro validation confirmed that MMRN1 overexpression enhanced GBM cell stemness and induced macrophage M2 polarization. MMRN1 is a critical BTSC-related biomarker that contributes to GBM progression by enhancing tumor stemness and modulating the immune microenvironment. Targeting MMRN1 May represent a promising therapeutic approach for GBM treatment.

Identification of neutrophil extracellular trap-related biomarkers in ulcerative colitis based on bioinformatics and machine learning

2025-06-20

Jiao Li , Yupei Liu , Zhiyi Sun +2 more | Frontiers in Genetics

Background The incidence of ulcerative colitis (UC) is rapidly increasing worldwide, but existing therapeutics are limited. Neutrophil extracellular traps (NETs), which have been associated with the development of various autoimmune … Background The incidence of ulcerative colitis (UC) is rapidly increasing worldwide, but existing therapeutics are limited. Neutrophil extracellular traps (NETs), which have been associated with the development of various autoimmune diseases, may serve as a novel therapeutic target for UC treatment. Methods Bioinformatics analysis was performed to investigate UC-related datasets downloaded from the GEO database, including GSE87466, GSE75214, and GSE206285. Differentially expressed genes (DEGs) related to NETs in UC patients and healthy controls were identified using Limma R package and WGCNA, followed by functional enrichment analysis. To identify potential diagnostic biomarkers, we applied the Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE) model, and Random Forest (RF) algorithm, and constructed Receiver Operating Characteristic (ROC) curves to evaluate accuracy. Additionally, immune infiltration analysis was conducted to identify immune cells potentially involved in the regulation of NETs. Finally, the expression of core genes in patients was validated using Quantitative real-time PCR (qRT-PCR), and potential therapeutic drugs for UC were explored through drug target databases. Result Differential analysis of transcriptomic sequencing data from UC samples identified 29 DEGs related to NETs. Enrichment analysis showed that these genes primarily mediate UC-related damage through biological functions such as leukocyte activation, migration, immune receptor activity, and the IL-17 signaling pathway. Three machine learning algorithms successfully identified core NETs-related genes in UC (IL1B, MMP9 and DYSF). According to ROC analysis, all three demonstrated excellent diagnostic efficacy. Additionally, Immune infiltration analysis revealed that the expression of these core genes was closely associated with neutrophils infiltration and CD4 + memory T cell activation, and negatively associated with M2 macrophage infiltration. qRT-PCR showed that the core genes were significantly overexpressed in UC patients. Gevokizumab, canakinumab and carboxylated glucosamine were predicted as potential therapeutic drugs for UC. Conclusion By combining three machine learning algorithms and bioinformatics, this research identified three hub genes that could serve as novel targets for the diagnosis and therapy of UC, which may provide valuable insights into the mechanism of NETs in UC and potential related therapies.

Neutrophil-driven tumor inflammation in breast cancer: Pathways and therapeutic implications: A narrative review

2025-06-20

Emmanuel Ifeanyi Obeagu | Medicine

Neutrophils, a key component of the innate immune system, have emerged as significant players in the tumor microenvironment (TME) of breast cancer. Traditionally recognized for their role in defending against … Neutrophils, a key component of the innate immune system, have emerged as significant players in the tumor microenvironment (TME) of breast cancer. Traditionally recognized for their role in defending against infections, neutrophils in cancer contribute to both tumor progression and suppression, depending on their activation state and the signals they receive. Neutrophil-driven inflammation within the TME is critical in promoting tumor growth, metastasis, and resistance to treatment. This review explores the complex role of neutrophils in breast cancer, emphasizing the mechanisms through which they influence tumor inflammation, including their interactions with other immune cells and the signaling pathways involved. Neutrophils can either support tumor progression by releasing pro-inflammatory cytokines, enzymes, and reactive oxygen species, or contribute to antitumor responses by directly killing cancer cells and stimulating adaptive immunity. The balance between these opposing functions is heavily influenced by the TME's cytokine milieu and neutrophil polarization. Key signaling pathways, such as the CXCR2-CXCL8 axis and interactions with tumor-associated macrophages, regulate neutrophil recruitment and activation in the TME, enhancing inflammation and tumorigenesis. Additionally, neutrophils' ability to form neutrophil extracellular traps further complicates their role, potentially promoting metastasis by trapping circulating tumor cells.

Prognostic implications of high- OXPHOS macrophages in gastric cancer: a single-cell transcriptomics and tumor microenvironment communication study

2025-06-20

Ziyuan Lin , Yunyu Xu , Xiaohe Xu +3 more | Frontiers in Oncology

Background Gastric cancer (GC) is characterized by heterogeneous tumor microenvironment (TME) with various cell types contributing to disease progression and patient outcomes. This study aims to dissect the single-cell transcriptomic … Background Gastric cancer (GC) is characterized by heterogeneous tumor microenvironment (TME) with various cell types contributing to disease progression and patient outcomes. This study aims to dissect the single-cell transcriptomic landscape of GC, highlighting the role of tumor-associated macrophages (TAMs) and establishing a novel prognostic signature based on high oxidative phosphorylation (OXPHOS) macrophages. Methods Single-cell sequencing data from paired GC and normal stomach tissues, obtained from the GEO database (GSE184198), were processed to reveal cellular heterogeneity and identify TAM subsets with high OXPHOS activity. Using the TCGA STAD dataset, survival analyses were conducted on 435 GC patients to establish a high-OXPHOS-macrophage-related prognostic signature. Results We identified eight distinct cell types within the GC TME, indicating significant cellular heterogeneity. Macrophages, particularly TAMs, were found in greater numbers in tumor tissue, with the C3 macrophage subset exhibiting the highest OXPHOS score. A 19-gene high-OXPHOS-macrophage-related prognostic signature was constructed, stratifying patients into different risk categories with significant survival differences (P&lt;0.05). NPC2, LY96, and TPP1 were identified as key macrophage-expressed markers, correlating with prognosis. Cell communication analysis revealed increased interaction in tumor tissues, especially involving NPC2, LY96, and TPP1 positive macrophages, which facilitated tumorigenesis and immune evasion. Conclusion The high-OXPHOS-macrophage-related prognostic signature derived from scRNA-seq data provides valuable insights into GC patient stratification. NPC2, LY96, and TPP1, highly expressed in TAMs, were implicated in promoting tumor growth and immune escape, offering potential targets for novel therapeutic interventions.

The Role of CAF‐derived Vitronectin in Promoting Colorectal Cancer Progression and Immunosuppression

2025-06-20

Jiahua Yu , Mengxi Xiu , Shijun Yu +3 more | Advanced Science

Abstract Cancer‐associated fibroblasts (CAFs) dominate the tumor stroma in colorectal cancer (CRC), fostering an immunosuppressive microenvironment that supports tumor growth, metastasis, and therapy resistance. Targeting CAF‐derived cytokines and secreted proteins … Abstract Cancer‐associated fibroblasts (CAFs) dominate the tumor stroma in colorectal cancer (CRC), fostering an immunosuppressive microenvironment that supports tumor growth, metastasis, and therapy resistance. Targeting CAF‐derived cytokines and secreted proteins offers potential new avenues for CRC treatment. Here, vitronectin (VTN) is identified as a significantly up‐regulated gene in CAFs, correlated with poor prognosis in CRC patients, through multi‐dataset analysis and multiplex immunofluorescence. Comprehensive analyses, including cytometry by time ‐of‐ flight (CyTOF), in vitro co‐culture assays, transgenic mouse models, and azoxymethane (AOM)/dextran sodium sulfate (DSS)‐induced CRC models, demonstrate that VTN enhances CRC proliferation, metastasis, and resistance to therapy. CyTOF analysis shows a reduced proportion of M2‐type macrophages in fibroblast‐specific VTN knockout mice ( Vtn fl/fl S100a4‐Cre + ), with VTN promoting M2 macrophage polarization in vitro. Mechanistically, VTN upregulates SLC6A8 expression in CRC cells and macrophages by enhancing FAK phosphorylation, which increases creatine and ATP uptake, promoting cancer progression and macrophage polarization. Targeted VTN knockout in fibroblasts significantly improves the efficacy of immunotherapies and reduces CRC progression. These findings highlight the dual role of CAF‐derived VTN in driving CRC malignancy and modulating immune responses, positioning VTN as a promising therapeutic target in CRC management.

Development of a prognostic immune cell-based model for ovarian cancer using multiplex immunofluorescence

2025-06-19

Sai Li , Bo Jiang , Hongying Zhou +3 more | Journal of Translational Medicine

Ovarian cancer is the most lethal gynecological malignancy, often diagnosed at advanced stages with poor prognosis. The tumor microenvironment (TME) plays a critical role in disease progression and treatment response. … Ovarian cancer is the most lethal gynecological malignancy, often diagnosed at advanced stages with poor prognosis. The tumor microenvironment (TME) plays a critical role in disease progression and treatment response. This study aimed to construct a prognostic model for ovarian cancer patients by evaluating the tumor immune landscape using multiplex immunofluorescence (mIF) staining, which focused on the spatial distribution and interactions of immune cells within the TME. Formalin-fixed paraffin-embedded (FFPE) tissues from 129 ovarian cancer patients were analyzed using mIF to assess the expression of PD-L1(Programmed death-ligand 1, PD-L1), CD8(Cluster of Differentiation 8, CD8), TOX (Thymocyte Selection-Associated HMG Box, TOX), CD68(Cluster of Differentiation 68, CD68), and CK (Cytokeratin, CK). The Vectra Polaris quantitative pathology imaging system and Inform software were employed for image and spatial analysis. The LASSO Cox regression model was used for feature selection, and Kaplan-Meier survival analysis was performed to evaluate the prognostic significance of immune cell markers. A nomogram was developed to predict overall survival (OS) based on clinical parameters and the Immune Cell Related Prognostic Index (ICRPI). High percentages of CD8 + T cells, CD68 + macrophages, and CD68 + PD-L1 + macrophages were significantly associated with poor OS. Moreover, a high percentage of CD8 + T cells, CD68 + macrophages was significantly associated with poor disease-free survival (DFS). Spatial analysis revealed that a higher average count of CD68 + PD-L1 + macrophages within 30 μm of CD8 + T cells correlated with worse prognosis. The ICRPI model, incorporating CD68+, CD68 + PD-L1+, and spatial variables, effectively stratified patients into high- and low-risk groups, with high-risk patients showing significantly poorer OS. This study highlights the prognostic value of immune cell spatial distribution in ovarian cancer. The ICRPI model, integrating immune cell markers and spatial analysis, provides a novel framework for predicting patient outcomes. Further validation in prospective studies is warranted to confirm the clinical utility of this model.

Extracellular matrix dynamics in tumor immunoregulation: from tumor microenvironment to immunotherapy

2025-06-19

Qin Hu , Yifei Zhu , Jie Mei +2 more | Journal of Hematology & Oncology

The extracellular matrix (ECM), closely linked to the dynamic changes in the tumor microenvironment (TME), plays a critical role in modulating tumor immunity. The dual role of the ECM in … The extracellular matrix (ECM), closely linked to the dynamic changes in the tumor microenvironment (TME), plays a critical role in modulating tumor immunity. The dual role of the ECM in tumor progression, encompassing both promotion and inhibition, is attributed to its components influencing immune cell activation, migration, and infiltration. This mechanism is intricately connected with the efficacy of immunotherapies. Currently, there is limited understanding of how ECM remodeling spatially and temporally coordinates with immune checkpoint inhibitors (ICIs) or adoptive cell therapies. Furthermore, strategies to selectively target pathological ECM components while preserving their homeostatic functions urgently require systematic investigation. In this review, we summarize current findings on the interplay between ECM and tumor immune regulation, with a particular focus on how key ECM components contribute to immune modulation. Furthermore, we discuss emerging strategies targeting ECM-related mechanisms to enhance the efficacy of immunotherapies, including approaches that remodel the ECM to improve immune infiltration and strategies that synergize with existing immunotherapies. By integrating these insights, we provide a perspective on leveraging ECM-targeted interventions to overcome immune evasion and optimize cancer immunotherapy outcomes.

Niche-Specific Reprogramming of Macrophages Reveals Myeloid Cell-Centric Targets During Pro-Senescence Therapy in Liver Cancer

2025-06-19

Efi Tsouri , Jing Xu , Eduardo Martin-Quintana +3 more | EMJ Hepatology

Nanoparticle‐Mediated CXCL12–CXCR4 Inhibition Reprograms Macrophages and Suppresses Gastric Carcinoma

2025-06-19

Qianqian Cao , Xiaolei Cheng , Rongbin Lv +7 more | Advanced Science

Abstract Gastric carcinoma (GC) remains a major global health challenge, requiring novel therapeutic approaches. This study investigates the efficacy of self‐assembled M2pep‐Cs NPs/Plerixafor nanoparticles in suppressing GC by targeting the … Abstract Gastric carcinoma (GC) remains a major global health challenge, requiring novel therapeutic approaches. This study investigates the efficacy of self‐assembled M2pep‐Cs NPs/Plerixafor nanoparticles in suppressing GC by targeting the CXCL12–CXCR4 signaling pathway and reprogramming tumor‐associated macrophages (TAMs) to enhance anti‐tumor immunity. The nanoparticles’ physicochemical properties and biocompatibility are assessed using transmission electron microscopy, dynamic light scattering, and biological assays. A GC mouse model is established, followed by histological and immunohistochemical analyses to evaluate tumor apoptosis and proliferation. Multi‐omics approaches, including transcriptomics, proteomics, and metabolomics, identify key genes and pathways affected by treatment. Flow cytometry and ELISA quantify immune activation markers; while, cell migration and invasion assays evaluate tumor suppression effects. The results demonstrate that M2pep‐Cs NPs/Plerixafor effectively modulates the tumor microenvironment, suppressing GC progression by reprogramming TAMs through CXCL12–CXCR4 inhibition, enhancing immune recognition and T cell responses. This study provides mechanistic insights and highlights the potential of nanoparticle‐based immunotherapy for GC, offering a promising avenue for clinical translation.

EZH2 regulates tumor-associated macrophages by the KDM6A-mediated inflammatory response in HPV16-positive cervical cancer

2025-06-19

Qing Tang , Ying Yang , Jianan Sun | Human Cell

Neuroprotective liver portal area macrophages attenuate hepatic inflammation

2025-06-19

Mengli Xu , Zheng Liu , Qi Pan +7 more | Nature Immunology

Scientometric analysis of lipid metabolism in macrophage polarization: 2013-2023

2025-06-19

Chenxiao Ye , Xiaosong Ru , Yong Guo | Frontiers in Oncology

Introduction Macrophage polarization plays a crucial role in the development of various diseases. Simultaneously, macrophage polarization is intimately related to lipid metabolism. To assess the emerging trend of lipid metabolism … Introduction Macrophage polarization plays a crucial role in the development of various diseases. Simultaneously, macrophage polarization is intimately related to lipid metabolism. To assess the emerging trend of lipid metabolism during macrophage polarization, the present study was carried out. Methods First, 472 publications that explored lipid metabolism during macrophage polarization were gathered using the Web of Science Core Collection database (WoSCC). The emerging trends were then described using CiteSpace. Results Between 2013 and 2023, 46 countries/regions involving 268 institutions carried out studies in this field. The largest number of publications was found in China. Additionally, the most recent burst keywords included “immunometabolism”, “foam cell formation”, and “pathway”, which represented the current frontiers of research. Discussion The detailed analysis of publications pertaining to lipid metabolism during macrophage polarization reveals the current research status and identifies its hotspots.

TYROBP overexpression alters macrophage phenotype and enhances pancreatic cancer stemness through STAT3 and PKM2 signaling

2025-06-18

Dingwen Zhong , Yonghui Liao , Wenhui Chen +4 more | Cellular Signalling

The development of a high-plex spatial proteomic methodology for the characterisation of the head and neck tumour microenvironment

2025-06-18

Chin Wee Tan , Naomi Berrell , Meg L. Donovan +7 more | npj Precision Oncology

Astragaloside IV: A Promising Drug to Prevent the Transition from Colitis to Colorectal Cancer

2025-06-18

Jiayu Ran , Yanling Ai , Jiyuan Ni +7 more | The American Journal of Chinese Medicine

Colorectal cancer (CRC) remains a major threat to health worldwide, partly due to the lack of effective treatments targeting the transition from inflammatory bowel disease (IBD) to malignancy. Astragaloside IV … Colorectal cancer (CRC) remains a major threat to health worldwide, partly due to the lack of effective treatments targeting the transition from inflammatory bowel disease (IBD) to malignancy. Astragaloside IV (AS-IV) is a major bioactive component from the traditional herb Astragalus membranaceus, and it has strong immunomodulatory and gastrointestinal protective effects. In this review, we evaluate the therapeutic potential and mechanisms of AS-IV in addressing the three hallmark pathological phases of colorectal cancer development: IBD-related inflammation, the transition from inflammation to cancer, and IBD-associated colorectal cancer (IBD-CRC). During the inflammatory phase, AS-IV promotes M2 macrophage polarization, reducing mucosal inflammation and repairing the intestinal barrier. In the transition from inflammation to cancer, AS-IV prevents IBD-CRC transition by targeting immune signaling pathways (e.g., NF-[Formula: see text]B and PPAR[Formula: see text] signaling pathways), gut microbiota, and oxidative stress. At the IBD-CRC stage, AS-IV can promote the polarization of M1 macrophages, thereby suppressing tumor growth, inducing apoptosis, inhibiting metastasis, and enhancing chemosensitivity. These findings highlight the potential of AS-IV to bidirectionally modulate the M1/M2 macrophage ratio and its role in the prevention and treatment of IBD-CRC. The multi-target therapeutic effects of AS-IV at various stages of IBD also provide new strategies to guide future drug development.

Cellular composition of tissue-resident monocyte-lineage cells reveal functional heterogeneity during inflammatory arthritis

2025-06-18

Yidan Wang , Samuel D. Dowling , Jessica Maciuch +7 more | bioRxiv (Cold Spring Harbor Laboratory)

ABSTRACT Tissue-resident monocyte-lineage cell (TRMC) are an extravascular population distinct from circulating monocytes and synovial macrophages and are critical for the development of inflammatory arthritis. However, the precise identities and … ABSTRACT Tissue-resident monocyte-lineage cell (TRMC) are an extravascular population distinct from circulating monocytes and synovial macrophages and are critical for the development of inflammatory arthritis. However, the precise identities and origins of TRMC subpopulations remain unclear. Here, we characterize the ontogeny of TRMC, which are comprised of bone-marrow (BM)-derived and an embryonic, long-lived population. Furthermore, we identified three TRMC subpopulations, distinguished by expression of TIM4, CX3CR1, and MHCII. Clodronate-laden liposome reduces the number of TRMC but does not impact the proportions or transcriptional profile of TRMC subpopulations at 7 days post administration. TIM4 + CX3CR1 + and TIM4 + TRMC represent long-lived population, whereas MHCII+ TRMC are BM-derived and dependent on Ccr2 during steady state. BM-derived TRMC expand and replenish the TIM4 + CX3CR1 + and TIM4 + TRMC compartments throughout the peak and plateau of inflammatory arthritis. These findings underscore the importance heterogeneity within TRMC and highlight their distinct responses to synovial disruption and potential roles in rheumatoid arthritis (RA).

HIF-1α+ CD4 T cells coordinate a tissue resident immune cell network in the lung

2025-06-17

J. Lima , Nivedya Swarnalekha , Ewelina M. Bartoszek +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Summary A deeper understanding of how tissue localized immune cells arise and function is critical for developing mucosal vaccines. Currently, there are no murine models that specifically target tissue T … Summary A deeper understanding of how tissue localized immune cells arise and function is critical for developing mucosal vaccines. Currently, there are no murine models that specifically target tissue T cells while leaving their lymphoid counterparts untouched. Here we leverage the observation that during influenza infection, HIF-1α regulatory activity is higher in the lung compared to lymph node CD4 T cells. Inducible deletion of Hif1a in CD4 T cells, at the onset of its activity in the lung, reduces the tissue resident T cell compartment with minimal impact on peripheral immunity. HIF-1α-active CD4 T cells occupy the border of tertiary lymphoid structures, where they coordinate an IL-21-dependent network of spatially co-localized immune cells including macrophages, NK cells and IgA+ B cells. A similar HIF-1α-dependent network is engaged in a lung adenocarcinoma model, highlighting a broader role for HIF-1α+ CD4 T cells in integrating protective immunity during infection and cancer.

Targeting tumor-associated macrophages in gastric cancer progression and therapy: insights from molecular mechanisms to therapeutic applications

2025-06-17

Chonghua Wan , Jie Deng , Yu Zhu +5 more | Frontiers in Pharmacology

Gastric cancer (GC) is the fifth most common malignant tumor that imposes heavily public health burdens worldwide. Systemic therapies for gastric cancer (GC), such as chemotherapy, targeted therapy, and immunotherapy, … Gastric cancer (GC) is the fifth most common malignant tumor that imposes heavily public health burdens worldwide. Systemic therapies for gastric cancer (GC), such as chemotherapy, targeted therapy, and immunotherapy, have undergone significant advancements. Nevertheless, the extensive application of anti-cancer agents has resulted in an increasing array of challenges related to drug resistance, presenting a substantial barrier in GC treatment. Tumor-associated macrophages (TAMs) as essential immunomodulators within the tumor immune microenvironment (TIME) of GC, providing novel therapeutic targets due to their capacity for plasticity in reaction to environmental signals. They create a complex network of communication with various immune and stromal cell types, thereby contributing to the immunosuppressive nature of the TME in GC. In this review, we establish the map of the origin and polarization of macrophages in GC. During the process of carcinogenesis, macrophages undergo dynamic phenotypic transitions. Additionally, the interactions between TAMs and tumor cells significantly influence the progression of GC, affecting tumor growth, metastasis, angiogenesis, and drug resistance. Furthermore, this intricate immunomodulatory axis notably enhances resistance to immunotherapy, suggesting that targeting TAMs presents substantial therapeutic opportunities for patients with GC. Approaches such as TAM elimination, TAM repolarization, and CAR-M therapy have been validated in numerous studies. We also elaborate on the challenges faced by the development of targeting TAMs, which may provide innovative perspectives on the GC treatment.

Succinate enhances mitochondrial metabolism and phagocytosis in human airspace monocytes

2025-06-17

Karen Slattery , Aisling Newing , John J. McGrath +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Abstract Airspace macrophages (AM) are crucial to host defence and to maintenance of lung homeostasis, with smoking drastically compromising these functions. Airspace monocytes, precursors of the differentiated AM, are found … Abstract Airspace macrophages (AM) are crucial to host defence and to maintenance of lung homeostasis, with smoking drastically compromising these functions. Airspace monocytes, precursors of the differentiated AM, are found in increased numbers in the lungs of smokers yet little is known about their metabolic regulation and function. Here, we develop a click chemistry-based single cell analysis platform to characterise human airspace monocytes and AM ex vivo , identifying distinct metabolic profiles and a key role for oxidative phosphorylation in supporting phagocytic function. While blood and newly recruited CD93+ airspace monocytes show low mitochondrial dependency, AM rely heavily on oxidative phosphorylation. Acute succinate supplementation enhanced mitochondrial metabolism and phagocytosis in monocytes and promoted their differentiation into highly oxidative macrophages with enhanced function. Succinate emerges as a promising candidate to restore lung immune function, particularly in the smoker’s lung where airspace monocytes are enriched. Overall, we identify mitochondrial metabolism as a key modulator of lung immune function and a target for therapeutic intervention, with potential applications in systemic monocyte-targeted therapies and metabolic preconditioning for adoptive cell therapies. One Sentence Summary : Mitochondrial metabolism regulates phagocytic function in human lung monocytes and macrophages and can be targeted using succinate. Graphical Abstract

Pro-inflammatory properties of M1 phenotypes of human macrophages: prolongation of myeloperoxidase-mediated oxidative stress

2025-06-17

Maria D. Yurkanova , Nastasia V. Kosheleva , Arina A. Teplova +2 more | Free Radical Research

Macrophages and neutrophils are the main immune cells of the acute stage of inflammation. Upon their activation, membrane-bound NADPH oxidase produces superoxide anion radical, which is converted to H2O2 by … Macrophages and neutrophils are the main immune cells of the acute stage of inflammation. Upon their activation, membrane-bound NADPH oxidase produces superoxide anion radical, which is converted to H2O2 by superoxide dismutase (SOD). In this study, we compared the production of hydrogen peroxide by two phenotypes of pro-inflammatory human M1 macrophages and neutrophils activated with phorbol-12-myristate 13-acetate. Macrophages were obtained from blood monocytes (monocyte-derived macrophages (MDM)) differentiated into MDM using GM- or M-CSF growth factors and polarized into the M1 state, receiving GM_M1, M_M1, respectively. The total level of H2O2 production measured in the presence of horseradish peroxidase differed significantly between two types of macrophages. Only GM_M1 macrophages had a level of H2O2 production comparable to neutrophils. GM_M1 appear at the site of inflammation after neutrophils, they continue the work of neutrophils in creating a pro-inflammatory environment: they produce several times more H2O2 and pro-inflammatory cytokines than M_M1, which arrive at inflammatory site later. Upon activation, MDM_M1 formed big blot-like and smaller dense spheroid-like aggregates. Activated neutrophils secrete the enzyme myeloperoxidase (MPO), which synthesizes the very potent oxidant hypochlorous acid (HOCl) only in the presence of H2O2. Neutrophils are short lived cells, MPO can use H2O2 produced by activated cultured MDM to synthesize HOCl at physiologically relevant concentrations to prolong oxidative stress.

Endothelial Cells retain inflammatory memory through chromatin remodeling

2025-06-17

Daniel Gonsales Spíndola , Samantha Clark , Amber Bahr +7 more | bioRxiv (Cold Spring Harbor Laboratory)

Sepsis survivors face a heightened risk of secondary infections and chronic vascular dysfunction despite clinical recovery, yet the underlying mechanisms remain poorly defined. Our study identifies a novel mechanism of … Sepsis survivors face a heightened risk of secondary infections and chronic vascular dysfunction despite clinical recovery, yet the underlying mechanisms remain poorly defined. Our study identifies a novel mechanism of endothelial inflammatory memory, wherein transient inflammatory exposure induces durable chromatin remodeling, priming endothelial cells for exaggerated responses to subsequent inflammatory insults. Utilizing a clinically relevant two-hit mouse model, cecal ligation and puncture (CLP) followed by secondary Streptococcus pneumoniae (SP) infection, we reveal persistent transcriptional activation in endothelial cells (ECs), characterized by amplified expression of inflammatory cytokines, adhesion molecules (e.g., ICAM-1), complement factors, and interferon-stimulated genes. Genome-wide ATAC-seq analyses demonstrated stable chromatin accessibility at key inflammatory loci, indicative of epigenetic priming. Mechanistically, we uncovered a critical role for the AP-1 transcription factor JunB in mediating this epigenetic remodeling. JunB knockdown attenuated chromatin accessibility and subsequent transcriptional amplification upon secondary challenge, pinpointing JunB-driven chromatin modifications as central to endothelial reprogramming. Our findings offer mechanistic insights into how transient inflammation creates lasting epigenetic states within the endothelium, highlighting JunB as a potential therapeutic target to mitigate chronic endothelial dysfunction and increased susceptibility to secondary infections post-sepsis.

Exploring T-cell metabolism in tuberculosis: development of a diagnostic model using metabolic genes

2025-06-16

Shoupeng Ding , Chun‐Xiao Huang , Jinghua Gao +3 more | European journal of medical research

Abstract Objectives The early diagnosis and immunoregulatory mechanisms of active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remain unclear, and the role of metabolic genes in host–pathogen interactions requires further … Abstract Objectives The early diagnosis and immunoregulatory mechanisms of active tuberculosis (ATB) and latent tuberculosis infection (LTBI) remain unclear, and the role of metabolic genes in host–pathogen interactions requires further investigation. Methods Single-cell RNA sequencing (scRNA-seq) was applied to analyze peripheral blood mononuclear cells (PBMCs) from 7 individuals, including 2 healthy controls (HC), 2 LTBI patients, and 3 ATB patients. We identified T-cell-associated metabolic differentially expressed genes (TCM–DEGs) through integrated differential expression analysis and machine learning algorithms (XGBoost, SVM–RFE, and Boruta). These TCM–DEGs were then used to construct a diagnostic model and evaluate its clinical applicability. Results The analysis revealed significant immunological alterations in TB patients, characterized by markedly elevated monocyte/macrophage populations ( p < 0.001) accompanied by reduced T and NK cell counts. Notably, LTBI cases demonstrated an intermediate CD4+/CD8+ T-cell ratio, indicative of dynamic immune homeostasis. The TB cohort exhibited increased inflammatory T-cell populations, while CD8+ T-cell-mediated MHC-I and BTLA signaling pathways were identified as key regulators of immune clearance and modulation. Transcriptomic profiling identified five metabolically significant differentially expressed genes (FHIT, MAN1C1, SLC4C7, NT5E, AKR1C3; p < 0.05) that effectively distinguish between latent tuberculosis infection (LTBI) and active tuberculosis (TB). The machine learning-driven diagnostic framework demonstrated remarkable consistency across independent validation cohorts (GSE39940, GSE39939), exhibiting AUC values spanning 0.867–0.873. Molecular subtyping analysis delineated two distinct TB phenotypes: an immune-activated M1 macrophage-dominant subtype and a CD8 + T-cell infiltrated immunophenotype. Clinical validation substantiated the differential expression patterns of T-cell-related metabolic differentially expressed genes (TCM–DEGs; p < 0.05), while the nomogram predictive model achieved exceptional discriminative capacity (C-index = 0.944), demonstrating superior clinical applicability through decision curve analysis. Conclusions Our findings reveal that TCM–DEGs critically regulate TB progression through immune–metabolic reprogramming and cell–cell communication networks. The developed diagnostic model and molecular subtyping strategy enable precise TB–LTBI differentiation and inform immunotherapy optimization.

Nanomedicine-mediated macrophage polarization enhances the iron-depleting effect of desferrioxamine for breast cancer immunotherapy

2025-06-16

Shiyu Chen , Weimin Yin , Hui Zhi +7 more | Journal of Controlled Release

The heterogeneous roles of neutrophils in gastric cancer: scaffold or target?

2025-06-16

Yansong Qin , Yunmei Liu , Peixin Dong +3 more | Cellular & Molecular Biology Letters

Gastric cancer (GC) is a significant challenge for global health. Neutrophils, the predominant white blood cells in the innate immune system, are increasingly becoming known as potential contributors to either … Gastric cancer (GC) is a significant challenge for global health. Neutrophils, the predominant white blood cells in the innate immune system, are increasingly becoming known as potential contributors to either tumor-promoting or tumor-suppressive activities within different tumor biology settings. This review highlights such dual roles of neutrophils in GC, where complex interactions occur within the tumor microenvironment. Specifically, we focus on the formation and function of neutrophil extracellular traps (NETs), which have emerged as critical players in GC progression. NETs influence key processes such as inflammation, angiogenesis, and metastasis. This review offers a comprehensive analysis of the polarization of neutrophils into two of its distinct subtypes, namely N1 and N2, which exert opposing influences on tumor biology. While N1 neutrophils exert anti-tumor properties, N2 neutrophils are generally regarded as pro-tumor. We uniquely discuss how these subtypes interact with cancer cells, affecting epithelial-mesenchymal transition and immune evasion mechanisms. These interactions change the tumor microenvironment and impact overall GC progression. In addition, we underscore the potential of neutrophils and their associated molecules as biomarkers and therapeutic targets. Specific neutrophil-derived markers and neutrophil-associated signaling pathways, along with their perspectives in personalized medicine that would pave the way for neutrophil-based anti-GC therapy, have been discussed in this review. Through the integration of these perspectives, we aim to guide future research involving neutrophils and their therapeutic implications, thus establishing strategies to precisely and effectively treat GC and improve prognosis.

Macrophage Signaling Pathways in Health and Disease: From Bench to Bedside Applications

2025-06-16

Yongquan Chi , Haipeng Jiang , Yue Yin +4 more | MedComm

ABSTRACT Macrophages exhibit remarkable functional plasticity by dynamically polarizing into proinflammatory or antiinflammatory subsets in response to microenvironmental cues. This duality underpins their pivotal roles in immune defense, tissue homeostasis, … ABSTRACT Macrophages exhibit remarkable functional plasticity by dynamically polarizing into proinflammatory or antiinflammatory subsets in response to microenvironmental cues. This duality underpins their pivotal roles in immune defense, tissue homeostasis, and disease progression; however, the molecular mechanisms governing their polarization and crosstalk across various pathologies remain incompletely defined. This review systematically delineates macrophage biology, emphasizing the interplay between subset‐specific signaling networks and their context‐dependent activation in both health and disease. The heterogeneity of macrophages is characterized by detailing the distinctions between tissue‐resident and monocyte‐derived origins, as well as their polarization states. Core pathways regulating phagocytosis, tissue repair, immune modulation, and neuroprotection are dissected, along with their dysregulation in autoimmune disorders, neurodegeneration, cancers, and cardiovascular diseases. Notably, microenvironmental factors such as damage‐associated molecular patterns, pathogen‐associated molecular patterns, and metabolic intermediates dynamically reshape macrophage phenotypes through NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation or signal transducer and activator of transcription (STAT)‐mediated transcriptional control. Preclinical and clinical evidence underscores potential therapeutic targets and emerging strategies. The significance of this review lies in its integrative analysis of signaling crosstalk, paradoxical pathway roles, and translational implications for precision therapies. These insights into macrophage functions and signaling pathways provide a robust foundation for future disease intervention and personalized medicine.

A temporal model of tumor-immune dynamics during the metastatic progression of high-grade serous ovarian cancer

2025-06-16

Donagh Egan , Kate Glennon , Ann Treacy +7 more | npj Precision Oncology

Abstract Patients with high-grade serous ovarian cancer (HGSOC) typically present with widespread metastasis, obscuring a temporal understanding of tumor-immune dynamics. To address this, we perform multi-site global proteomics alongside matched … Abstract Patients with high-grade serous ovarian cancer (HGSOC) typically present with widespread metastasis, obscuring a temporal understanding of tumor-immune dynamics. To address this, we perform multi-site global proteomics alongside matched immunohistochemistry (IHC) for CD4⁺ and CD8⁺ tumor-infiltrating lymphocytes (TILs) in patient samples. We order the protein expression profiles using an unbiased pseudotime analysis, recapitulating clinical observations of metastatic progression, and providing a framework to explore tumor-immune dynamics from localized to metastatic disease. Metastatic progression correlates with immune cell infiltration, the recruitment of regulatory T cells (Tregs) to counterbalance γδ T cell abundance, and an increased abundance of exhausted CD8⁺ T cells. The accumulation of Tregs at metastatic sites correlates with SNX8 expression, a critical regulator of the STING pathway. In early-stage tumors, keratin-expressing cancer cells recruit Tregs via MHC class II, fostering an inflammatory phenotype with limited IFNγ production and non-clonally expanded T cells. Together, our findings reveal novel mechanisms of immune escape associated with both localized disease and metastatic progression in HGSOC.

Immunostimulatory effects of IL-12 targeted pH-responsive nanoparticles in macrophage-enriched 3D immuno-spheroids in vitro model

2025-06-16

Maria José Silveira , Cláudia Martins , Ana Patrícia Cardoso +5 more | Drug Delivery and Translational Research

Abstract Metastatic colorectal cancer (CRC) has the dismal 5-year survival rate of only 14%, and immunotherapies fail to improve the patient outcome. One reason for the poor response rate is … Abstract Metastatic colorectal cancer (CRC) has the dismal 5-year survival rate of only 14%, and immunotherapies fail to improve the patient outcome. One reason for the poor response rate is the slightly acidic (~ 6.5) immunosuppressive microenvironment. Interleukin 12 (IL-12) is a highly potent pro-inflammatory cytokine that can stimulate tumor immune cells and reverse immunosuppression by inducing interferon gamma (IFN-γ) expression. However, its clinical applications are hindered by systemic side effects. In this study, we developed pH-responsive polymeric nanoparticles (NPs) encapsulating IL-12 to enhance its therapeutic efficacy into the tumor microenvironment (TME). IL-12-loaded pH-responsive NPs induced antitumoral pro-inflammatory response in macrophages at pH ~ 6.5, determined by increased IFN-γ levels and nitric oxide (NO) release, without affecting metabolic activity. In contrast, IL-12-loaded pH non-responsive PLGA NPs showed much lower macrophage activation. To validate the specificity and efficacy in a complex immune-rich microenvironment, we developed a novel CRC 3D immuno-spheroid by incorporating human monocyte-derived macrophages with tumor cells in collagen, mimicking CRC spatial organization and extracellular matrix. The interaction of IL-12 pH-responsive NPs induced macrophage polarization, by providing a reduction of M2-like markers (CD14 + CD163+) while increasing pro-inflammatory M1-like counterparts (CD14 + CD86+). Moreover, IL-12 pH-responsive NPs increased IFN-γ levels and reduced anti-inflammatory IL-10 secretion. Overall, this study provides two major findings (1) a pH-responsive NP system to effectively deliver IL-12 to the TME and reprogram local macrophages into pro-inflammatory phenotype; (2) a macrophage-enriched human 3D immuno-spheroid in vitro system as a tool to test the effectivity of immunomodulatory NPs.

In vivo labelling resolves distinct temporal, spatial, and functional properties of tumour macrophages, and identifies subset-specific effects of PD-L1 blockade

2025-06-16

Colin Y. C. Lee , Isaac Dean , Nathan Richoz +7 more | Cancer Immunology Research

Abstract Tumour-associated macrophages (TAMs) are a universal feature of cancers but variably influence outcome and treatment responses. Here, we used a photoconvertible mouse to distinguish newly entering, monocyte-derived (md)TAMs that … Abstract Tumour-associated macrophages (TAMs) are a universal feature of cancers but variably influence outcome and treatment responses. Here, we used a photoconvertible mouse to distinguish newly entering, monocyte-derived (md)TAMs that were enriched at the tumour core, from resident-like (r)TAMs that localised with fibroblasts at the tumour–normal interface. The mdTAM pool was highly dynamic and continually replenished by circulating monocytes. Upon tumour entry, these monocytes differentiated down two divergent fate trajectories distinguished by the expression of MHC class II. MHC-II+ mdTAMs were functionally distinct from MHC-II– mdTAMs, demonstrating increased capacity for endocytosis and FcγR-mediated phagocytosis, as well as pro-inflammatory cytokine production. Both mdTAM subsets showed reduced expression of inflammatory transcripts and increased expression of PD-L1 with increasing tumour dwell-time. Treatment with anti-PD-L1 skewed mdTAM differentiation towards the MHC-II+ fate and attenuated the anti-inflammatory effects of the tumour environment. Anti-PD-L1 enhanced mdTAM–CD4+ T-cell interactions, establishing an IFNγ-CXCL9/10-dependent positive feedback loop. Altogether, these data resolve distinct temporal, spatial and functional properties of TAMs, and provide evidence of subset-specific effects of PD-L1 blockade.

Tumor-associated neutrophils and neutrophil extracellular traps in lung cancer: antitumor/protumor insights and therapeutic implications

2025-06-16

Milad Sheervalilou , Mostafa Ghanei , Masoud Arabfard | Medical Oncology

Overexpression of BPIFB4 Alleviates COPD Inflammatory Damage by Inhibiting M1 Macrophage Activation via the PI3K/AKT Pathway

2025-06-16

Lili Xue , Jingran Xu , Hui Gong +7 more | Lung

Lipid Nanoparticles for Driving Macrophages to Promote Proinflammatory Cytokine Upregulation

2025-06-16

Shireesha Manturthi , Amandine Courtemanche , Zafar H. Zaidi +7 more | ACS Applied Nano Materials

Zirconium-89-Oxine Cell Tracking by PET Reveals Preferential Monocyte Recruitment to Cancer and Inflammation over Macrophages

2025-06-15

Sho Koyasu , Hannah A. Minor , Kingsley O. Asiedu +2 more | Pharmaceuticals

Background/Objectives: Cell-based therapies have become increasingly important in the treatment of cancers and inflammatory diseases; however, therapies utilizing monocyte-macrophage lineage cells remain relatively underexplored. Non-invasive cell tracking allows a better … Background/Objectives: Cell-based therapies have become increasingly important in the treatment of cancers and inflammatory diseases; however, therapies utilizing monocyte-macrophage lineage cells remain relatively underexplored. Non-invasive cell tracking allows a better understanding of the fate of such cells, which is essential for leveraging their therapeutic potential. Here, we employed a Zirconium-89 (89Zr)-oxine cell labeling method to compare the trafficking of monocytes and macrophages in vivo. Methods: Mouse bone marrow-derived monocytes and macrophages were each labeled with 89Zr-oxine and evaluated for their viability, radioactivity retention, chemotaxis, and phagocytic function in vitro. Labeled cells were intravenously administered to healthy mice and to murine models of granuloma and syngeneic tumors. Cell migration was monitored using microPET/CT, while cell recruitment to the lesions was further assessed via ex vivo biodistribution and flow cytometry. Results: Labeled cells exhibited similar survival and proliferation to unlabeled cells for up to 7 days in culture. While both maintained phagocytic function, monocytes showed higher CCL2-driven chemotaxis compared to macrophages. 89Zr-oxine PET revealed initial cell accumulation in the lungs, followed by their homing to the liver and spleen within 2-24 h, persisting through the 5-day observation period. Notably, monocytes trafficked to the liver and spleen more rapidly than macrophages. In both inflammation and cancer models, monocytes demonstrated higher accumulation at the lesion sites compared to macrophages. Conclusions: This study demonstrates the usefulness of 89Zr-oxine PET in tracking monocyte-macrophage lineage cells, highlighting their distinct migration patterns and providing insights that could advance monocyte-centered cell therapies.

N1 and N2 Neutrophils in Breast Cancer: Mechanisms, Clinical Relevance, and Therapeutic Potential

2025-06-15

Emmanuel Ifeanyi Obeagu , Isaac Isiko | International Journal of Medical Sciences and Pharma Research

Neutrophils are key components of the immune system and play a significant role in the tumour microenvironment (TME) of breast cancer. These cells can undergo polarization into two distinct phenotypes: … Neutrophils are key components of the immune system and play a significant role in the tumour microenvironment (TME) of breast cancer. These cells can undergo polarization into two distinct phenotypes: N1 and N2 neutrophils. N1 neutrophils are typically associated with antitumor immunity, characterized by the production of pro-inflammatory cytokines and reactive oxygen species (ROS), which help inhibit tumour growth and metastasis. On the other hand, N2 neutrophils contribute to tumour progression by secreting immunosuppressive cytokines, promoting angiogenesis, and enhancing metastatic spread. The balance between these two phenotypes can have significant implications for cancer progression and treatment outcomes in breast cancer patients. The polarization of neutrophils is regulated by a complex network of cytokines, growth factors, and signalling pathways in the TME. Factors such as IL-12, IFN-γ, and GM-CSF promote N1 polarization, while IL-10, TGF-β, and VEGF are key drivers of N2 polarization. These pathways influence neutrophil recruitment, activation, and survival within the TME. Strategies targeting neutrophil polarization could offer new opportunities for breast cancer treatment, particularly for patients with aggressive or metastatic disease. Keywords: N1 Neutrophils, N2 Neutrophils, Breast Cancer, Tumor Microenvironment, Immunotherapy

N1 and N2 Neutrophil Polarization in Breast Cancer: Predictive Value for Treatment Outcomes

2025-06-15

Emmanuel Ifeanyi Obeagu , Isaac Isiko | International Journal of Medical Sciences and Pharma Research

Neutrophils, the most abundant white blood cells in the immune system, play a crucial role in breast cancer progression through their ability to polarize into two distinct phenotypes: N1 and … Neutrophils, the most abundant white blood cells in the immune system, play a crucial role in breast cancer progression through their ability to polarize into two distinct phenotypes: N1 and N2. N1 neutrophils are considered antitumor effector cells that promote immune responses and inhibit tumour growth, while N2 neutrophils support tumour progression by promoting inflammation, immune suppression, and metastasis. The balance between these two phenotypes within the tumour microenvironment (TME) can significantly influence breast cancer development and response to treatment. The polarization of neutrophils in the TME is influenced by various factors, including cytokines, growth factors, and interactions with other immune cells. N1 neutrophils exhibit pro-inflammatory and cytotoxic properties that help limit tumour growth, while N2 neutrophils contribute to an immunosuppressive microenvironment that facilitates cancer progression and therapy resistance. Studies suggest that an increased presence of N1 neutrophils correlates with improved prognosis and response to therapies, whereas a predominance of N2 neutrophils is often associated with poor treatment outcomes and increased metastatic potential. This review examines the mechanisms underlying neutrophil polarization and the implications of these phenotypes on treatment responses in breast cancer. Keywords: N1 neutrophils, N2 neutrophils, neutrophil polarization, breast cancer, treatment outcomes