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As an important innate immune cell in the body, macrophages have a strong ability to phagocytic tumor cells and maintain the innate immune response. Tumor-associated macrophages play a more prominent role in regulating tumor immunity and are currently an important target of antitumor immunity. As a new type of antitumor therapy, tumor immunotherapy has great potential, combined chemotherapy, targeting and other therapeutic means can significantly enhance the antitumor therapy effect. At present, a number of natural products have been proved to have significant immunomodulatory and antitumor effects, and have become a hot field of antitumor immunity research. Studies have found that a variety of natural products, such as polysaccharides, flavonoids, saponins, lactones, and alkaloids, can induce the polarization of M1 macrophages, inhibit the polarization of M2 macrophages, and regulate the expression of immune-related cytokines by targeting specific signaling pathways to enhance the killing effect of macrophages on tumor cells and improve the tumor immune microenvironment, and finally better play the antitumor immune function. In this paper, by summarizing the research results of the specific mechanism of natural products targeting tumor-associated macrophages to exert antitumor immunity in recent years, we discussed the aspects of natural products targeting tumor-associated macrophages to enhance antitumor immunity, in order to provide a new research idea for tumor immunotherapy and further improve the effectiveness of clinical antitumor therapy., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Colorectal cancer (CRC) exhibits a substantial morbidity and mortality rate, with its aetiology and pathogenesis remain elusive. It holds significant importance within the tumour microenvironment (TME) and exerts a crucial regulatory influence on tumorigenesis, progression, and metastasis. TAMs possess the capability to foster CRC pathogenesis, proliferation, invasion, and metastasis, as well as angiogenesis, immune evasion, and tumour resistance. Furthermore, TAMs can mediate the prognosis of CRC. In this paper, we review the mechanisms by which natural compounds target TAMs to exert anti-CRC effects from the perspective of the promotional effects of TAMs on CRC, mainly regulating the polarization of TAMs, reducing the infiltration and recruitment of TAMs, enhancing the phagocytosis of macrophages, and regulating the signalling pathways and cytokines, and discuss the potential value and therapeutic strategies of natural compounds-targeting the TAMs pathway in CRC clinical treatment., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s).)

Tumor-associated macrophages (TAMs) drive the protumorigenic responses and facilitate tumor progression via matrix remodeling, angiogenesis, and immunosuppression by interacting with extracellular matrix proteins via integrins. However, the expression dynamics of integrin and its correlation with TAM functional programming in the tumors remain unexplored. In this study, we examined surface integrins' role in TAM recruitment and phenotypic programming in a 4T1-induced murine breast tumor model. Our findings show that integrin α5β1 is upregulated in CD11b+Ly6Chi monocytes in the bone marrow and blood by day 10 after tumor induction. Subsequent analysis revealed elevated integrin α5β1 expression on tumor-infiltrating monocytes (Ly6ChiMHC class II [MHCII]low) and M1 TAMs (F4/80+Ly6ClowMHCIIhi), whereas integrin αvβ3 was predominantly expressed on M2 TAMs (F4/80+Ly6ClowMHCIIlow), correlating with higher CD206 and MERTK expression. Gene profiling of cells sorted from murine tumors showed that CD11b+Ly6G-F4/80+α5+ TAMs had elevated inflammatory genes (IL-6, TNF-α, and STAT1/2), whereas CD11b+Ly6G-F4/80+αv+ TAMs exhibited a protumorigenic phenotype (IL-10, Arg1, TGF-β, and STAT3/6). In vitro studies demonstrated that blocking integrin α5 and αv during macrophage differentiation from human peripheral blood monocytes reduced cell spreading and expression of CD206 and CD163 in the presence of specific matrix proteins, fibronectin, and vitronectin. Furthermore, RNA sequencing data analysis (GEO dataset: GSE195857) from bone marrow-derived monocytes and TAMs in 4T1 mammary tumors revealed differential integrin α5 and αv expression and their association with FAK and SRC kinase. In line with this, FAK inhibition during TAM polarization reduced SRC, STAT1, and STAT6 phosphorylation. In conclusion, these findings underscore the crucial role of integrins in TAM recruitment, polarization, and reprogramming in tumors., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Tumor-associated microglia and macrophages (TAM) make up the largest immune cell population in the glioblastoma (GBM) tumor microenvironment. Given the heterogeneity and plasticity of TAMs in the GBM tumor microenvironment, understanding the context-dependent cancer cell-TAM symbiotic interaction is crucial for understanding GBM biology and developing effective therapies. In a recent issue of Cell, Kloosterman and colleagues identified a subpopulation of glycoprotein nonmetastatic melanoma protein Bhigh lipid-laden microglia and macrophages (LLM) in GBM. Mesenchymal-like GBM cells help generate the LLM phenotype. Reciprocally, LLMs are epigenetically rewired to recycle myelin and transfer the lipid from myelin to cancer cells, fueling mesenchymal-like GBM progression in a liver X receptor/ABCA1-dependent manner. Together, leveraging LLMs opens new therapeutic possibilities for rewiring the metabolism-mediated tumor-TAM interaction during GBM progression., (©2024 American Association for Cancer Research.)

The complex heterogeneity of tumor microenvironment (TME) of triple-negative breast cancer (TNBC) presents a significant obstacle to cytotoxic immune response and successful treatment, building up one of the most hostile oncological phenotypes. Among the most abundant TME components, tumor-associated macrophages (TAMs) have pivotal pro-tumoral functions, involving discordant roles for the nuclear factor kappa-B (NF-κB) transcription factors and directing to higher levels of pathway complexity. In both resting macrophages and TAMs, we recently revealed the existence of the uncharacterized NF-κB p65/p52 dimer. In the present study, we demonstrated its enhanced active nuclear localization in TAMs and validated selected immune target genes as directly regulated by dimer binding on DNA sequences. We demonstrated by ChIP-qPCR that p65/p52 enrichment on HSPG2 and CSF-1 regulatory regions is strictly dependent on macrophage polarization and tumor environment. Our data provide novel mechanisms of transcriptional regulation in TAMs, orchestrated by the varied and dynamic nature of NF-κB combinations, which needs to be considered when targeting this pathway in cancer therapies. Our results offer p65/p52, together with identified regulatory regions on genes impacting macrophage behavior and tumor biology, as novel molecular targets for TNBC, aimed at modulating TAMs functions towards anti-tumoral phenotypes and thus improving cancer treatment outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In the tumor microenvironment, macrophages exhibit different phenotypes and functions in response to various signals, playing a crucial role in the initiation and progression of tumors. Several studies have indicated that intervention in the functions of different phenotypes of tumor-associated macrophages causes significant changes in the crosstalk between tumor cells and immune-related cells, such as T, NK, and B cells, markedly altering the course of tumor development. However, only a few specific therapeutic strategies targeting macrophages are yet available. This article comprehensively reviews the molecular biology mechanisms through which tumor-associated macrophages mediate the crosstalk between tumor cells and immune-related cells. Also, various treatment methods currently used in clinical practice and those in the clinical trial phase have been summarized, and the novel strategies for targeting tumor-associated macrophages have been categorized accordingly., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Glioblastoma (GBM), known as the most malignant and common primary brain tumor of the central nervous system, has finite therapeutic options and a poor prognosis. Studies have shown that host intestinal microorganisms play a role in the immune regulation of parenteral tumors in a number of different ways, either directly or indirectly. However, the potential impact of gut microbiota on tumor microenvironment, particularly glioma immunological milieu, has not been clarified exactly. In this study, by using an orthotopic GBM model, we found gut microbiota dysbiosis caused by antibiotic cocktail treatment boosted the tumor process in vivo. An obvious change that followed gut microbiota dysbiosis was the enhanced percentage of M2-like macrophages in the TME, in parallel with a decrease in the levels of gut microbial metabolite, short-chain fatty acids (SCFAs) in the blood and tumor tissues. Oral supplementation with SCFAs can increase the proportion of M1-like macrophages in the TME, which improves the outcomes of glioma. In terms of mechanism, SCFAs-activated glycolysis in the tumor-associated macrophages may be responsible for the elevated M1 polarization in the TME. This study will enable us to better comprehend the "gut-brain" axis and be meaningful for the development of TAM-targeting immunotherapeutic strategies for GBM patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Manganese (Mn) play a crucial role in various biological processes in the body. Studies have primarily focused on their ability to enhance immune cell function and activation against tumors, particularly in dendritic cells (DCs), macrophages, and T cells. Tumor-associated macrophages (TAMs) are often the most abundant immune cell population present in the tumor microenvironment (TME). Thus, it would be valuable to investigate the mechanism by which Mn 2+ regulates TAMs' involvement in anti-tumor immunity, as it be crucial for advancing our understanding of cancer biology and developing new treatments for cancer. Here, in the present study we discovered that Mn 2+ treatment led to a significant increase in KLRG1 + macrophages (KLRG1 + Mφ) in tumor tissues, and most of these cells exhibited an M1 phenotype. Knocking down KLRG1 in macrophages not only impaired their ability to induce downstream anti-tumor immunity of adaptive immune cells, but also impaired their direct cytotoxicity against tumor cells. Moreover, the changes in the polarization phenotype of KLRG1 + macrophages further lead to T cell proliferation and the polarization of CD4 + T cells towards a Th1 phenotype, thereby establishing a foundation for the antitumor immune response. Our study expands the understanding of the anti-tumor mechanism of Mn 2+ and demonstrates, for the first time, that Mn 2+ can regulate the function of KLRG1 + Mφ to participate in anti-tumor activities. These findings suggest that KLRG1 may represent a promising target for developing new tumor therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Cytokines, tumor cells, and tumor-associated macrophages play crucial roles in the composition of glioma tissue. Studies have demonstrated that certain cytokines can induce M2 polarization of tumor-associated macrophages and contribute to the progression of glioma. Nonetheless, the intricate molecular interactions among cytokines, glioma cells, and tumor-associated macrophages remain largely unexplored. To investigate this cross-talk, a combination of RNA-sequencing, chromatin immunoprecipitation, immunoprecipitation, exosome isolation, and biological experiments were employed. Treatment with IL-6 significantly increased circ-001422 expression in glioma cells. A poorer prognosis was associated with elevated levels of circ-001422 in glioma tissues. Circ-001422 was transcribed directly by STAT3 through binding to its promoter. Circ-001422 exerted cancer-promoting functions when co-cultured with M2 macrophages. Furthermore, glioma cells were found to transfer circ-001422 to macrophages via an exosomal pathway, promoting M2 polarization. Mechanically, circ-001422 interacted with p300, resulting in STAT3 acetylation, thus promoting nuclear localization and transcriptional activity of STAT3/NF-κB and M2 macrophage polarization. In conclusion, glioma cells released exosomes enriched with circ-001422, which in turn induce M2 macrophage polarization by activating the STAT3/NF-κB pathway, thereby enhancing the aggressive characteristics of glioma cells. Targeting circ-001422 may represent a potential therapeutic approach for glioma., Competing Interests: Competing interests The authors declare no competing interests. Ethics The Human Research Ethics Review Committee of Guizhou Medical University approved the application of these clinical samples, which was performed according to the tenets of the Declaration of Helsinki. The process of animal experiments was approved by Animal Ethics Committee of Guizhou Medical University., (© 2024. The Author(s).)

Purpose: Tumor-associated macrophages (TAMs) play a crucial role in shaping various tumor microenvironments. However, their recruitment in Wilms tumor (WT), the predominant malignant renal tumor in children, has been inadequately explored. This retrospective cohort study involved the analysis of 148 WT samples to investigate the recruitment and polarization typing of TAMs in WT tissues., Methods: WT tissues underwent Western blotting (WB), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and immunofluorescence (IF) to measure the expression of TAM markers CD68, CD86, and CD163. Statistically analyze the relationship between TAM recruitment levels and patient clinical characteristics, and use Kaplan-Meier curves and the log-rank test to evaluate the association between TAM levels and survival outcomes., Results: The findings indicated a positive correlation between the recruitment levels of total macrophages (Mtotal) and M2 tumor-associated macrophages (M2 TAM) in both chemotherapy and non-chemotherapy groups with the clinical stage. Elevated recruitment of Mtotal and M2 TAM in tumor tissues was linked to a poorer prognosis. Notably, patients with persistently higher recruitment of M2 TAM following preoperative chemotherapy exhibited the worst prognosis., Conclusions: The recruitment and polarization typing of TAM exhibit significant differences in WT patients with various stages and prognosis outcomes, suggesting a potential avenue for future diagnosis and treatment of WT., Competing Interests: The authors declare no conflicts of interest., (Copyright: © 2024 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Macrophages, abundant in tumors, are classified as M1 or M2 types with M2 dominating the tumor microenvironment. Shifting macrophages from M2 to M1 using exosomes is a promising intervention. The properties of exosomes depend on their source cells. M1-exosomes are expected to polarize macrophages towards M1 phenotype. We compared M1-exosomes and M0-exosomes' effects on M2 macrophage polarization. The RAW264.7 cells were cultured and one group of them was exposed to LPS. The serum-free medium was collected and exosomes were extracted. Exosomes were analyzed by scanning and transmission electron microscopy, dynamic light scattering and Western blot. Subsequently, M1 or M0 exosomes were applied to M2 macrophages induced by IL4. The macrophages polarization, including M1 and M2 genes and surface markers expression, cytokines secretion, and phagocytosis ability were evaluated. It was demonstrated that M1-exosomes induced macrophage polarization toward the M1 phenotype, characterized by an upregulation of M1-specific markers and a downregulation of M2 markers. Furthermore, the secretion of TNF-α was increased, while the secretion of IL-10 was decreased. The phagocytosis ability of M1-exosome-treated macrophages was also augmented. This research suggested that M1-exosomes might be promising candidates for modulating immune response in situations marked by an overabundance of M2 polarization, like in cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The anti-tumor immune response is greatly hindered by the protumor polarization of tumor-associated macrophages (TAMs). Cancer-related inflammation plays a central role in TAMs protumor polarization. Our study explored the unique positive feedback loop between inflammasome and complement in TAMs. The present study identified NOD-like receptors family pyrin domain containing 12 (NLRP12) formed positive feedback with C1qA and drove TAMs protumor polarization via the LILRB4/NF-κB pathway. In addition, NLRP12 was predominantly expressed in TAMs and was associated with poorer prognosis in lung adenocarcinoma (LUAD) patients. Knocking down LILRB4 inhibited TAMs protumor polarization. NLRP12-overexpressing TAMs promoted tumor cells' malignant progression and inhibited T cells' proliferation and cytotoxic function. Lastly, NLRP12 knockout (NLRP12 -/- ) reversed macrophage polarization, enhanced T-cell anti-tumor immunity, and suppressed tumor growth. Our findings highlighted the essential role of NLRP12/C1qA positive feedback loop and the LILRB4/NF-κB pathway in promoting TAMs protumor polarization. Inhibition of NLRP12 suppressed tumor development and promoted immune response. NLRP12 may be a promising target for LUAD immunotherapy., Competing Interests: Declarations Conflict of interest The authors declare no conflict of interests. Ethical approval All animal experiments were approved by the Committee of Animal Care and Use of Renmin Hospital of Wuhan University, under the consent number WDRM 20240405B, and were performed following the Guide for the Care and Use of Laboratory Animals. Consent to publish Not applicable., (© 2024. The Author(s).)

In this article, we comment on the article by Huang et al . The urgent development of new therapeutic strategies targeting macrophage polarization is critical in the fight against liver cancer. Tumor-associated macrophages (TAMs), primarily of the M2 subtype, are instrumental in cellular communication within the tumor microenvironment and are influenced by various signaling pathways, including the wingless/integrated (Wnt) pathway. Activation of the Wnt signaling pathway is pivotal in promoting M2 TAMs polarization, which in turn can exacerbate hepatocarcinoma cell proliferation and migration. This manuscript emphasizes the burgeoning significance of the Wnt signaling pathway and M2 TAMs polarization in the pathogenesis and progression of liver cancer, highlighting the potential therapeutic benefits of inhibiting the Wnt pathway. Lastly, we point out areas in Huang et al 's study that require further research, providing guidance and new directions for similar studies., Competing Interests: Conflict-of-interest statement: Tam PKH and Chen Y have received research funding from Macau Science and Technology Development Fund., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

The efficacy of immune checkpoint inhibitors in the treatment of hepatocellular carcinoma (HCC) remains limited, highlighting the need for further investigation into the mechanisms underlying treatment resistance. Accumulating evidence indicates that tumor-associated macrophages (TAM) within the tumor microenvironment demonstrate a key role in immune evasion and treatment resistance. This study explored the role of TAMs in the HCC tumor microenvironment. Our findings reveal that TAMs expressing CX3C motif chemokine receptor 1 (CX3CR1) induced T-cell exhaustion through IL27 secretion in orthotopic models of HCC following treatment with anti-PD1. Moreover, we identified prostaglandin E2 (PGE2), released by immune-attacked tumor cells, as a key regulator of TAM transition to a CX3CR1+ phenotype. To augment the therapeutic response to anti-PD1 therapy, we propose targeting CX3CR1+ TAMs in addition to anti-PD1 therapy. Our study contributes to the understanding of the role of TAMs in cancer immunotherapy and highlights potential clinical implications for HCC treatment. The combination of targeting CX3CR1+ TAMs with anti-PD1 therapy holds promise for enhancing the efficacy of immunotherapeutic interventions in patients with HCC., (©2024 American Association for Cancer Research.)

α5-nicotinic acetylcholine receptor (α5-nAChR) plays a vital part in lung adenocarcinoma (LUAD). However, it is not comprehensively understood that how the α5-nAChR affects LUAD. Through diverse bioinformatics analyses and immunohistochemistry, the expressions of α5-nAChR and SOX2 as well as their relations were dissected. α5-nAChR regulated the differentiation of monocytes into M2 macrophages by targeting the STAT3/SOX2/CSF-1 signaling in the coculture system by western blotting and ChIP. α5-nAChR-mediated macrophage-mediated LUAD cell migration via SOX2/CSF-1 signaling in the cocultured medium. Correlations of α5-nAChR, SOX2 and M2 phenotype tumor-associated macrophages (TAMs) were validated in mouse LUAD models and clinical samples. α5-nAChR expression was connected to SOX2 expression, smoking and bad prognosis of LUAD among clinical samples. Nicotine-induced SOX2 expression was mediated by α5-nAChR via STAT3. Additionally, SOX2-mediated macrophage colony-stimulating factor (CSF-1) expression contributed to LUAD progression in vitro. Furthermore, α5-nAChR expression was strongly linked to pSTAT3, SOX2 and M2 macrophage marker CD206 expression and negatively correlated with M1 macrophage marker CD86 expression in vivo. It is indicated that M2 macrophages are mediated by the new α5-nAChR /SOX2/CSF-1 axis in nicotine-related LUAD, which is a potential therapeutic strategy for cancer., (© 2024. The Author(s).)

Tumor-associated macrophages (TAMs) are a phenotypically diverse, highly plastic population of cells in the tumor microenvironment (TME) that have long been known to promote cancer progression. In this review, we summarize TAM ontogeny and polarization, and then explore how TAMs enhance tumor cell migration through the TME, thus facilitating metastasis. We also discuss how chemotherapy and host factors including diet, obesity, and race, impact TAM phenotype and cancer progression. In brief, TAMs induce epithelial-mesenchymal transition (EMT) in tumor cells, giving them a migratory phenotype. They promote extracellular matrix (ECM) remodeling, allowing tumor cells to migrate more easily. TAMs also provide chemotactic signals that promote tumor cell directional migration towards blood vessels, and then participate in the signaling cascade at the blood vessel that allows tumor cells to intravasate and disseminate throughout the body. Furthermore, while chemotherapy can repolarize TAMs to induce an anti-tumor response, these cytotoxic drugs can also lead to macrophage-mediated tumor relapse and metastasis. Patient response to chemotherapy may be dependent on patient-specific factors such as diet, obesity, and race, as these factors have been shown to alter macrophage phenotype and affect cancer-related outcomes. More research on how chemotherapy and patient-specific factors impact TAMs and cancer progression is needed to refine treatment strategies for cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Friedman-DeLuca, Karagiannis, Condeelis, Oktay and Entenberg.)

Introduction: Macrophages are essential in maintaining homeostasis, combating infections, and influencing the process of various diseases, including cancer. Macrophages originate from diverse lineages: Notably, tissue-resident macrophages (TRMs) differ from hematopoietic stem cells and circulating monocyte-derived macrophages based on genetics, development, and function. Therefore, understanding the recruited and TRM populations is crucial for investigating disease processes., Methods: By searching literature databses, we summarized recent relevant studies. Research has shown that tumor-associated macrophages (TAMs) of distinct origins accumulate in tumor microenvironment (TME), with TRM-derived TAMs closely resembling gene signatures of normal TRMs., Results: Recent studies have revealed that TRMs play a crucial role in cancer progression. However, organ-specific effects complicate TRM investigations. Nonetheless, the precise involvement of TRMs in tumors is unclear. This review explores the multifaceted roles of TRMs in cancer, presenting insights into their origins, proliferation, the latest research methodologies, their impact across various tumor sites, their potential and strategies as therapeutic targets, interactions with other cells within the TME, and the internal heterogeneity of TRMs., Conclusions: We believe that a comprehensive understanding of the multifaceted roles of TRMs will pave the way for targeted TRM therapies in the treatment of cancer., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

This study develops a prognostic model to predict metastasis and prognosis in colorectal cancer liver metastases by identifying distinct macrophage subsets. Using scRNA-seq data from primary colorectal cancer and liver metastases, we dissected the cellular landscape to find unique macrophage subpopulations, particularly EEF1G + macrophages, which were prevalent in liver metastases. The study leveraged data from GSE231559, TCGA, and GEO databases to construct an 8-gene risk model named EMGS, based on the EEF1G + macrophage gene signature. Patients were divided into high-risk and low-risk groups using the median EMGS score, with the high-risk group showing significantly worse survival. This group also demonstrated upregulated pathways associated with tumor progression, such as epithelial-mesenchymal transition and angiogenesis, and downregulated metabolic pathways. Moreover, the high-risk group presented an immunosuppressive microenvironment, with a higher TIDE score indicating lower effectiveness of immunotherapy. The study identifies potential drugs targeting the high-risk group, suggesting therapeutic avenues to improve survival. Conclusively, the EMGS score identifies colorectal cancer patients at high risk of liver metastases, highlighting the role of specific macrophage subsets in tumor progression and providing a basis for personalized treatment strategies., (© 2024. The Author(s).)

Aberrant Notch, which is a defining feature of triple-negative breast cancer (TNBC) cells, regulates intercellular communication in the tumor immune microenvironment (TIME). This includes tumor-associated macrophage (TAM) recruitment through Notch-dependent cytokine secretion, contributing to an immunosuppressive TIME. Despite the low response rate of TNBC to immune checkpoint blockade (ICB), here, we report that inhibition of Notch-driven cytokine-mediated programs reduces TAMs and induces responsiveness to sequentially delivered ICB. This is characterized by the emergence of GrB + cytotoxic T lymphocytes (CTLs) in the primary tumor. A more impressive effect of sequential treatment is observed in the lung where TAM depletion and increased CTLs are accompanied by near-complete abolition of metastases. This is due to (i) therapeutic reduction in Notch-dependent, prometastatic circulating factors released by the primary tumor, and (ii) elevated PD ligand 1 (PD-L1) in lung metastases, rendering them profoundly sensitive to ICB. These findings highlight the potential of combination cytokine inhibition and ICB as an immunotherapeutic strategy in TNBC.

Tumor-associated macrophages (TAMs) are prime therapeutic targets due to their pro-tumorigenic functions, but varying efficacy of macrophage-targeting therapies highlights our incomplete understanding of how macrophages are regulated within the tumor microenvironment (TME). The circadian clock is a key regulator of macrophage function, but how circadian rhythms of macrophages are influenced by the TME remains unknown. Here, we show that conditions associated with the TME such as polarizing stimuli, acidic pH, and lactate can alter circadian rhythms in macrophages. While cyclic AMP (cAMP) has been reported to play a role in macrophage response to acidic pH, our results indicate pH-driven changes in circadian rhythms are not mediated solely by cAMP signaling. Remarkably, circadian disorder of TAMs was revealed by clock correlation distance analysis. Our data suggest that heterogeneity in circadian rhythms within the TAM population level may underlie this circadian disorder. Finally, we report that circadian regulation of macrophages suppresses tumor growth in a murine model of pancreatic cancer. Our work demonstrates a novel mechanism by which the TME influences macrophage biology through modulation of circadian rhythms., (© 2024. The Author(s).)

Invasion and metastasis are hallmarks of cancer. In addition to the well-recognized hematogenous and lymphatic pathways of metastasis, cancer cell dissemination can occur via the transcoelomic and perineural routes, which are typical of ovarian and pancreatic cancer, respectively. Macrophages are a universal major component of the tumor microenvironment and, in established tumors, promote growth and dissemination to secondary sites. Here, we review the role of tumor-associated macrophages (TAMs) in cancer cell dissemination and metastasis, emphasizing the diversity of myeloid cells in different tissue contexts (lungs, liver, brain, bone, peritoneal cavity, nerves). The generally used models of lung metastasis fail to capture the diversity of pathways and tissue microenvironments. A better understanding of TAM diversity in different tissue contexts may pave the way for tailored diagnostic and therapeutic approaches., (© 2024. The Author(s).)

Background / Purpose: The progression of epithelial to mesenchymal tissue (EMT) is a highly intricate process that facilitates the transformation of cancer cells, allowing them to changeover their characteristic epithelial properties to mesenchymal attributes. This notable change empowers the cells with enhanced mobility and the ability to migrate to distant locations. Furthermore, it is imperative to adopt the idea of macrophage tumor cell fusion to achieve comprehensive considerate of this phenomenon. Our primary objective was to conduct a thorough investigation of macrophage-restricted antigens expression, specifically CD68 and CD163, in malignant epithelial cells of oral cavity squamous cell carcinoma (OSCC) to elucidate aforementioned perceptions., Materials and Methods: CD68 and CD163 immunohistochemical expression were assessed in oral squamous cell carcinoma (OSCC), encompassing both the neoplastic cells and the tumor-associated macrophages (TAMs)., Results: Both CD68 and CD163 antigens were revealed in OSCC malignant epithelial cells in a granular cell pattern, localized in membrane and cytoplasm of tumor cells respectively as well as in the infiltrating TAMs., Conclusion: The macrophage antigens were not limited to the infiltrating tumor-associated macrophages (TAMs), but were also observed in a substantial proportion of OSCC malignant epithelial cells within the tumor parenchyma. This particular expression pattern may represent a subset of tumor cells that have undergone an epithelial to a mesenchymal phenotypic transition. In addition, fusion of macrophages with tumor cells cannot be excluded; both might be associated with increased metastatic activity of OSCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Overcoming resistance to immunotherapy in cancer is challenging due, in part, to tumor-associated macrophages (TAMs) co-expressing T cell immunoglobulin and mucin domain-containing 3 (TIM3) and V-domain immunoglobulin suppressor of T cell activation (VISTA) in tumor microenvironments (TME) with sparse T cell infiltration. In a recent article, Vanmeerbeek et al. found that blocking TIM3 or VISTA on IL-4-supported TAMs, in combination with paclitaxel (PTX), reprogrammed TAMs to attack cancer cells, highlighting a potential new therapeutic strategy., Competing Interests: Declaration of interests None declared by authors., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with β3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cell migration and promotes their differentiation toward an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intratumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10, and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to anti-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of anti-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression colocalized with myeloid cell infiltration. scRNA-Seq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the oncoimmunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential therapeutic target to enhance immunotherapy in patients with OvCa.

Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b +  F4/80 + TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity., (© 2024. The Author(s).)

Gliomas are the most prevailing brain malignancy in both children and adults. Microglia, which are resident in the central nervous system (CNS), are distributed throughout the brain and serve an important role in the immunity of the CNS. Microglial cells exhibit varying phenotypic and metabolic properties during different stages of glioma development, making them a highly dynamic cell population. In particular, glioma‑associated microglia/macrophages (GAMs) can alter their metabolic characteristics and influence malignancies in response to the signals they receive. The significance of macrophage metabolic reprogramming in tumor growth is becoming increasingly acknowledged in recent years. However, to the best of our knowledge, there is currently a scarcity of data from investigations into the lipid metabolic profiles of microglia/macrophages in the glioma setting. Therefore, the present review aims to provide a thorough review of the role that lipid metabolism serves in tumor‑associated macrophages. In addition, it outlines potential targets for therapy based on lipid metabolism. The present review aims to serve as a reference source for future investigations into GAMs.

Macrophages have crucial roles in immune responses and tumor progression, exhibiting diverse phenotypes based on environmental cues. In the present study, the impact of cinobufagin (CB) on macrophage polarization and the consequences on tumor‑associated behaviors were investigated. Morphological transformations of THP‑1 cells into M0, M1 and M2 macrophages were observed, including distinct changes in the size, shape and adherence properties of these cells. CB treatment inhibited the viability of A549 and LLC cells in a concentration‑dependent manner, with an IC 50 of 28.8 and 30.12 ng/ml, respectively. CB at concentrations of <30 ng/ml had no impact on the viability of M0 macrophages and lung epithelial (BEAS‑2B) cells. CB influenced the expression of macrophage surface markers, reducing CD206 positivity in M2 macrophages without affecting CD86 expression in M1 macrophages. CB also altered certain expression profiles at the mRNA level, notably downregulating macrophage receptor with collagenous structure (MARCO) expression in M2 macrophages and upregulating tumor necrosis factor‑α and interleukin‑1β in both M0 and M1 macrophages. Furthermore, ELISA analyses revealed that CB increased the levels of pro‑inflammatory cytokines in M1 macrophages and reduced the levels of anti‑inflammatory factors in M2 macrophages. CB treatment also attenuated the migration and invasion capacities of A549 and LLC cells stimulated by M2 macrophage‑conditioned medium. Additionally, CB modulated peroxisome proliferator‑activated receptor γ (PPARγ) and MARCO expression in M2 macrophages and epithelial‑mesenchymal transition in A549 cells, which was partially reversed by rosiglitazone, a PPARγ agonist. Finally, CB and cisplatin treatments hindered tumor growth in vivo , with distinct impacts on animal body weight and macrophage marker expression in tumor tissues. In conclusion, the results of the present study demonstrated that CB exerted complex regulatory effects on macrophage polarization and tumor progression, suggesting its potential as a modulator of the tumor microenvironment and a therapeutic for cancer treatment.

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients., (© 2024. The Author(s).)

Summary: Taurine (Tau) has been found to inhibit triple-negative breast cancer (TNBC) invasion and metastasis. However, its effect on tumor-promoting macrophages and tumor suppressor macrophages in breast cancer progression remains unknown. In this study, we investigated the effects of Tau on macrophage polarization and its role in TNBC cell growth, invasion, and metastasis. We induced human THP-1 monocytes to differentiate into M2 macrophages through exogenous addition of interleukin-4. We used the TNBC cell lines MDA-MB-231 and BT-549 cultured in a conditioned medium from M2 macrophages to investigate the effect of Tau on tumor growth and invasion. We analyzed macrophage subset distribution, M1 and M2 macrophage-associated markers, and mRNA expression by quantitative polymerase chain reaction. We also detected the PTEN-PI3K/Akt/mTOR signaling pathway that mediates M1 macrophage to suppress tumor invasion using western blotting. Our results showed that Tau inhibits breast cancer metastasis to the lungs in vivo and cell invasion by altering the polarization of tumor-associated macrophage in vitro. In addition, Tau can up-regulate PTEN expression, suppress the PI3K-Akt signaling pathway, and promote the M1 polarization of macrophages, which ultimately inhibits the metastasis of TNBC cells. Our findings suggest that Tau inhibits the activation of the PI3K-Akt-mTOR signaling pathway by up-regulating PTEN , promotes the proportion of M1 macrophages in tumor-associated macrophage, and suppresses the invasion and metastasis of TNBC. This provides a potential therapeutic approach to influence cancer progression and metastasis., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Cutaneous and subcutaneous mast cell tumors (MCTs) are common canine neoplasms characterized by variable biological behavior. Tumor-associated macrophages (TAMs) and tumor-infiltrating lymphocytes (TILs) can be effective prognostic markers in numerous human neoplasms and are increasingly investigated in dogs. The aim of this study was to characterize immune cells in canine MCTs and their relationship with histological location (cutaneous, subcutaneous) and histologic nodal metastatic status (HN0-3). Thirty-eight MCTs (26 cutaneous, 12 subcutaneous) from 33 dogs with known sentinel lymph node (SLN) metastatic status were immunolabeled for Iba1 (macrophages), CD20 (B cells), CD3 (T cells), and Foxp3 (regulatory T cells). Semiquantitative scoring of interstitial and perivascular CD3+, CD20+, and Foxp3+ cells and morphological evaluation of Iba1+ cells were performed. For each marker, the percent immunopositive area was evaluated by image analysis. All MCTs were diffusely infiltrated by Iba1+ cells and variably infiltrated by CD20+, CD3+, and rare Foxp3+ cells. Stellate/spindle Iba1+ cells were associated with HN2 and HN3 SLNs. Perivascular Foxp3+ cells, CD3+ cells, and percent CD3+ areas were increased in subcutaneous MCTs. Interstitial CD3+ cells were increased in cutaneous MCTs with HN0 SLNs. No differences in CD20+ cells were identified between cutaneous and subcutaneous MCTs and among SLN classes. MCTs were markedly infiltrated by TAMs and variably infiltrated by TILs. Stellate/spindle morphology of TAMs associated with HN2 and HN3 SLNs is suggestive of a pro-tumoral (M2) phenotype. Cutaneous and subcutaneous MCTs have different tumor-immune microenvironments, and T-cell infiltration might contribute to prevention of nodal metastatic spread of cutaneous MCTs., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

HCC, the most common type of primary liver cancer, is a leading cause of cancer-related mortality worldwide. Although the advancement of immunotherapies by immune checkpoint inhibitors (ICIs) that target programmed cell death 1 or programmed cell death 1-ligand 1 has revolutionized the treatment for HCC, the majority is still not beneficial. Accumulating evidence has pointed out that the potent immunosuppressive tumor microenvironment in HCC poses a great challenge to ICI therapeutic efficacy. As a key component in tumor microenvironment, tumor-associated macrophages (TAMs) play vital roles in HCC development, progression, and ICI low responsiveness. Mechanistically, TAM can promote cancer invasion and metastasis, angiogenesis, epithelial-mesenchymal transition, maintenance of stemness, and most importantly, immunosuppression. Targeting TAMs, therefore, represents an opportunity to enhance the ICI therapeutic efficacy in patients with HCC. While previous research has primarily focused on biochemical cues influencing macrophages, emerging evidence highlights the critical role of biophysical signals, such as substrate stiffness, topography, and external forces. In this review, we summarize the influence of biophysical characteristics within the tumor microenvironment that regulate the phenotype and function of TAMs in HCC pathogenesis and progression. We also explore the possible mechanisms and discuss the potential of manipulating biophysical cues in regulating TAM for HCC therapy. By gaining a deeper understanding of how macrophages sense and respond to mechanical forces, we may potentially usher in a path toward a curative approach for combinatory cancer immunotherapies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

The problem of liver cancer is becoming increasingly important due to the epidemic of metabolic diseases and persistent high alcohol consumption. This determines great attention to the development and improvement of methods for early diagnosis and treatment of liver cancer. Huang et al presented a study in the World Journal of Gastroenterology , in which they showed that the use of the traditional Chinese medicine Calculus bovis (CB) can suppress tumor growth in mice by inhibiting M2 tumor-associated macrophages (TAM) through modulating the activity of the Wnt/β-catenin pathway. The interaction of CB components with the Wnt/β-catenin pathway, M2 TAM polarization, and tumor dynamics were studied using network pharmacology, transcriptomics, and molecular docking. It is now generally accepted that the polarization of TAM and the differentiation of the functions of M1 and M2 phagocytes are of great importance for the progression of neoplasms. It is assumed that M2 TAM promote proliferation and migration of tumor cells. Attempts to medicinally influence the Wnt/β-catenin pathway in order to modulate phagocyte polarization now belong to one of the most promising areas of immunotherapy of oncological diseases. Undoubtedly, the work of the Chinese authors deserves attention and further development., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Cancer immunotherapy, particularly immune checkpoint inhibitors (ICBs) such as anti-PD-1 antibodies, has revolutionised cancer treatment, although response rates vary among patients. Previous studies have demonstrated that caerin 1.1 and 1.9, host-defence peptides from the Australian tree frog, enhance the effectiveness of anti-PD-1 and therapeutic vaccines in a murine TC-1 model by activating tumour-associated macrophages intratumorally., Methods: We employed a murine B16 melanoma model to investigate the therapeutic potential of caerin 1.1 and 1.9 in combination with anti-CD47 and a therapeutic vaccine (triple therapy, TT). Tumour growth of caerin-injected primary tumours and distant metastatic tumours was assessed, and survival analysis conducted. Single-cell RNA sequencing (scRNAseq) of CD45 + cells isolated from distant tumours was performed to elucidate changes in the tumour microenvironment induced by TT., Results: The TT treatment significantly reduced tumour volumes on the treated side compared to untreated and control groups, with notable effects observed by Day 21. Survival analysis indicated extended survival in mice receiving TT, both on the treated and distant sides. scRNAseq revealed a notable expansion of conventional type 1 dendritic cells (cDC1s) and CD4 + CD8 + T cells in the TT group. Tumour-associated macrophages in the TT group shifted toward a more immune-responsive M1 phenotype, with enhanced communication observed between cDC1s and CD8 + and CD4 + CD25 + T cells. Additionally, TT downregulated M2-like macrophage marker genes, particularly in MHCIIhi and tissue-resident macrophages, suppressing Cd68 and Arg1 expression across all macrophage types. Differential gene expression analysis highlighted pathway alterations, including upregulation of oxidative phosphorylation and MYC target V1 in Arg1 hi macrophages, and activation of pro-inflammatory pathways in MHCII hi and tissue-resident macrophages., Conclusion: Our findings suggest that caerin 1.1 and 1.9, combined with immunotherapy, effectively modulate the tumour microenvironment in primary and secondary tumours, leading to reduced tumour growth and enhanced systemic immunity. Further investigation into these mechanisms could pave the way for improved combination therapies in advanced melanoma treatment., (© 2024. The Author(s).)

Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) promote immune evasion, cancer cell proliferation, and metastasis. Ongoing research is focused on finding ways to prevent tumor growth by inhibiting TAM polarization, which has shown a correlation with unfavorable prognosis in clinical studies. Pancreatic adenocarcinoma up-regulated factor (PAUF) is a protein secreted from pancreatic cancer (PC) and acts as a TME modulator that affects the TME by acting on not only cancer cells but also stromal cells and immune cells. Tumor cells can evade the immune system by PAUF binding to Toll-like receptor (TLR) in monocytes, as this research shows. In this study, the examination centered around the recruitment of human monocytes by PAUF and the subsequent differentiation into macrophages. In an in vitro chemotaxis assay, PAUF induced chemotactic migration of TLR2-mediated monocytes. In addition, PAUF induced differentiation of monocytes into M2 macrophages, which was verified based on expressing surface markers and cytokines and morphological analysis. The inhibition of T cell proliferation and function was observed in differentiated M2 macrophages. To conclude, these findings indicate that PAUF functions as a promoter of cancer progression by regulating the recruitment and differentiation of macrophages within TMEs, ultimately causing immunosuppression.

Background: The role of HOXA9 requires investigations in pancreatic ductal adenocarcinoma (PDAC) as HOXA9 inhibitors are being developed. HOXA9 might attract CD163 expressed tumor associated macrophages (TAM) and could affect PDAC prognosis. This work aims to study the expression and relevance of HOXA9 and CD163 in PDAC progression., Materials and Methods: Selected 98 PDAC and 98 adjacent non tumor tissues as a control group were immunostained with HOXA9 and CD163 antibodies., Results: PDAC displayed highly significant higher HOXA9 staining intensity, percent and H score values than control group. HOXA9 staining of PDAC cases showed significant associations with poor prognostic indicators including larger tumor size, higher grade and advanced stage. PDAC showed highly significant differences regarding CD163 macrophage-specific staining intensity, percent and H score values than control group. CD163 showed significant higher expressions with larger tumor size, higher histological grade and advanced stage group. HOXA9 staining in PDAC showed highly significant direct correlations with CD163 positive macrophages. Follow up of PDAC cases revealed that high median H score of HOXA9 and CD163 were significantly associated with worse overall survival. CD163 was an independent prognostic marker of worse survival., Conclusions: In conclusion, HOXA9 could potentiate PDAC progression by stimulating CD163 expressed TAM attraction in tumors. HOXA9 and CD163 could participate in PDAC therapy. HOXA9 and CD163 could be predictors of worse prognosis and shorter survival in PDAC., (© 2024. The Author(s).)

Background: Reoperation is a treatment option for recurrent gliomas, yet factors impacting survival following reoperation remain poorly defined. Tumor immunity is profoundly associated with disease progression. Here, we analyze the immune status characteristics and their prognostic implications in recurrent gliomas., Methods: Intratumoral and peripheral immune characteristics between primary and recurrent gliomas were compared by conducting immunohistological staining and hematological examination with our in-house samples, and analyzing bulk and single-cell sequencing data from publicly available sources. Survival analysis was conducted to identify immunological markers with prognostic significances., Results: We observed a significant reduction in peripheral lymphocyte count, while an elevation in neutrophil-to-lymphocyte ratio (NLR) and red cell distribution width-to-platelet ratio (RPR) in patients with recurrent gliomas than in newly-diagnosed patients. Higher NLR and RPR indicated worse survival following reoperation in recurrent patients. Transcriptomic and immunohistological analysis showed an increased infiltration of tumor-associated macrophages (TAMs) and CD8 + T cell in recurrent gliomas compared to primary gliomas in both IDH-wildtype and mutant subtypes. Moreover, the abundance of TAMs emerged as an independent indicator for an inferior prognosis in recurrent gliomas. Single-cell profiling revealed a significant heterogeneity in the phenotypes of TAMs between primary and recurrent gliomas. Notably, TAMs enriched in recurrent gliomas exhibited elevated expression of interferon-γ-induced genes, multiple immunosuppressive molecules (TGFB1, CD276), and increased activity in glycose and lipid metabolism, indicating metabolic reprogramming., Conclusion: Recurrent gliomas demonstrate augmented immune cell infiltration, but they fail to overcome TAMs-induced immunosuppression. Immunosuppressive indices, including TAM abundance, peripheral NLR and RPR, have prognostic implications for recurrent gliomas., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Tumor-associated macrophages (TAMs) have been demonstrated to be associated with tumor progression. However, the different subpopulations of TAMs and their roles in gastric cancer (GC) remain poorly understood. This study aims to assess the effects of Spi-1 proto-oncogene (SPI1) + CD68 + TAMs in GC., Methods: The distribution of SPI1 + CD68 + TAMs in GC tissue was estimated by immunohistochemistry, immunofluorescence, and flow cytometry. Single-cell transcriptome analysis and multiplex fluorescence immunohistochemistry were applied to explore the role of SPI1 + CD68 + TAMs in an immune contexture. SPI1 overexpression or knockdown cells were constructed to evaluate its role in macrophage polarization and angiogenesis in vitro and in vivo. Chromatin immunoprecipitation was used to verify the mechanism of SPI1 transcriptional function. The effect of combined antiangiogenic and immunotherapy was further validated using mouse peritoneal metastasis models., Results: Single-cell transcriptome analysis and immunohistochemistry demonstrated that SPI1 was expressed in macrophages, with a higher enrichment in metastatic lesions than in primary tumors. Higher SPI1 + CD68 + TAMs infiltration was associated with poor overall survival. Mechanically, SPI1 promoted the M2-type macrophage polarization. SPI1 could bind to the promoter of vascular endothelial growth factor A and facilitate angiogenesis. Moreover, the level of SPI1 + CD68 + TAMs infiltration was closely related to the efficacy of immunotherapy, especially when combined with antiangiogenic therapy., Conclusions: The present study showed that SPI1 + CD68 + TAMs are a promising biomarker for predicting prognosis, antiangiogenic drug sensitivity, and combination target of immunotherapy in patients with GC., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell-derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target.

Cancer immunotherapy has demonstrated remarkable efficacy in the treatment of cancer, and it has been successfully applied in the treatment of various solid tumors. However, the response rates to immunotherapy in patients with ovarian cancer remain modest because of the immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) represent the predominant myeloid cell population within the TME, which adopt the protumorigenic M2 phenotype and are blinded by the "don't eat me" signals from tumor cells. These characteristics of TAMs result in insufficient phagocytic activation. In this study, we constructed a SIM@TR-NP-mediated combination therapy of sonodynamic and immunotherapy. SIM@TR-NPs were modified by engineered macrophage membranes with overexpressed sialic acid-binding Ig-like lectin 10 (Siglec-10), and were internally loaded with sonosensitizer 4,4',4'',4'''-(porphine-5,10,15,20-tetrayl)tetrakis(benzoic acid) and immune adjuvant resiquimod. SIM@TR-NPs can block "don't eat me" signals to enhance macrophage phagocytosis and trigger the polarization of TAMs toward the M1 phenotype, thereby improving the immunosuppressive TME. Simultaneously, upon ultrasound irradiation, SIM@TR-NP-mediated sonodynamic therapy (SDT) triggered immunogenic cell death in tumor cells, in combination with TAM-based immunotherapy, transforming the "immune cold tumor" into an "immune hot tumor". SIM@TR-NP-mediated sonodynamic immunotherapy exhibited potent antitumor efficacy in ovarian cancer and exhibited substantial potential for improving the immunosuppressive TME. This study presents an emerging therapeutic regimen for ovarian cancer that synergizes TAM-based antitumor immunotherapy and SDT.

Tumor-associated macrophages (TAMs) have been implicated as a tumor microenvironment (TME) cell population, which may be playing a vital role in the inhibition of effective T cell responses in the prostate TME. In this manuscript, we leverage a novel microscale cell culture platform, known as Stacks, to investigate mono-, co-, and tri-culture TME models comprised of prostate tumor cell lines, primary macrophages, and autologous T cells from patients with prostate cancer. Through multiplexed analysis of these multi-cellular prostate tumor models, we capture a dynamic interaction between primary TAMs and activated T cells that resulted in reciprocal proinflammatory activation of both cell populations upon interaction. These findings suggest that activated T cells are capable of reprogramming immunosuppressive TAMs in the context of prostate tumor models and that TAM reprogramming may play a key supportive role in restoring proinflammatory T cell tumor responses in the prostate TME., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Malassezia globosa is a lipophilic basidiomycetous yeast that occurs abundantly in breast tumors and that may contribute to a shortened overall survival of breast cancer (BRAC) patients, suggesting that the yeast may participate in the carcinogenesis of BRAC. However, the mechanisms involved in the M. globosa -based acceleration of BRAC are unknown. Here, we show that M. globosa can colonize mammary tissue in 7,12-dimethylbenz[a] anthracene-induced mice. The abundance of M. globosa shortened the overall survival and increased the tumor incidence. Transcriptome data illustrated that IL-17A plays a key role in tumor growth due to M. globosa colonization, and tumor-associated macrophage infiltration was elevated during M. globosa colonization which triggers M2 polarization of macrophages via toll-like receptors 4/nuclear factor kappa-B (Nf-κB) signaling. Our results show that the expression of sphingosine kinase 1 (Sphk1) is increased in breast tumors after inoculation with M. globosa . Moreover, we discovered that Sphk1-specific small interfering RNA blocked the formation of lipid droplets, which can effectively alleviate the expression of the signal transducer and activator of the transcription 3 (STAT3)/Nf-κB pathway. Taken together, our results demonstrate that M. globosa could be a possible factor for the progression of BRAC. The mechanisms by which M. globosa promotes BRAC development involve the IL-17A/macrophage axis. Meanwhile, Sphk1 overexpression was induced by M. globosa infection, which also promoted the proliferation of MCF-7 cells.IMPORTANCELiterature has suggested that Malassezia globosa is associated with breast tumors; however, this association has not been confirmed. Here, we found that M. globosa colonizes in breast fat pads leading to tumor growth. As a lipophilic yeast, the expression of sphingosine kinase 1 (Sphk1) was upregulated to promote tumor growth after M. globosa colonization. Moreover, the IL-17A/macrophages axis plays a key role in mechanisms involved in the M. globosa -induced breast cancer acceleration from the tumor immune microenvironment perspective., Competing Interests: The authors declare no conflict of interest.

Unfolded protein response (UPR) is a central stress response pathway that is hijacked by tumor cells for their survival. Here, we find that IRE1α signaling, one of the canonical UPR arms, is increased in prostate cancer (PCa) patient tumors. Genetic or small molecule inhibition of IRE1α in syngeneic mouse PCa models and an orthotopic model decreases tumor growth. IRE1α ablation in cancer cells potentiates interferon responses and activates immune system related pathways in the tumor microenvironment (TME). Single-cell RNA-sequencing analysis reveals that targeting IRE1α in cancer cells reduces tumor-associated macrophage abundance. Consistently, the small molecule IRE1α inhibitor MKC8866, currently in clinical trials, reprograms the TME and enhances anti-PD-1 therapy. Our findings show that IRE1α signaling not only promotes cancer cell growth and survival but also interferes with anti-tumor immunity in the TME. Thus, targeting IRE1α can be a promising approach for improving anti-PD-1 immunotherapy in PCa., (© 2024. The Author(s).)

Non-muscle-invasive bladder cancer (NMIBC) presents management challenges due to its high recurrence rate and a complex tumor microenvironment (TME). This study investigated the effects of OncoTherad® (MRB-CFI1) nanoimmunotherapy on the TME of BCG-unresponsive NMIBC, focusing on alterations in monoamine oxidases (MAO-A and MAO-B) and immune markers: CD163, FOXP3, CD8, and CX3CR1. A comparative analysis of immunoreactivities was made before and after OncoTherad® treatment and an immune score (IS) was established to evaluate the correlation between immunological changes and clinical outcomes. Forty bladder biopsies of twenty patients were divided into 2 groups (n = 20/group): 1 (pre-treatment biopsies); and 2 (post-treatment biopsies). Our results showed stable MAO-A levels but a significant (p < 0.05) decrease in MAO-B immunoreactivity after treatment, suggesting OncoTherad®'s efficacy in targeting the tumor-promoting and immunosuppressive functions of MAO-B. Significant (p < 0.05) reductions in CD163 and FOXP3 immunoreactivities were seen in post-treatment biopsies, indicating a decreased presence of M2 macrophages and Tregs. Corroborating with these results, we observed reductions in tumor histological grading, focality and size, factors that collectively enhanced recurrence-free survival (RFS) and pathological complete response (PCR). Moreover, elevated IFN-γ immunoreactivities in treated biopsies correlated with increased counts of CD8 + T cells and higher CX3CR1 expression, underscoring OncoTherad®'s enhancement of cytotoxic T cell functionality and overall antitumor immunity. The IS revealed improvements in immune responses post-treatment, with higher scores associated with better RFS and PCR outcomes. These findings validate OncoTherad®'s capability to modify the bladder cancer microenvironment favorably, promoting effective immune surveillance and response., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Although oncolytic adenoviruses are widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains to be studied. Here, we demonstrate that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory T cells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, thymosin alpha 1 (Tα1) reprograms "M2-like" TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADV Tα1 is constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8 + T cells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing oncolytic engineered adenoviruses., Competing Interests: Declaration of interests K.L., J.W., C.J., L.K., H.C., X.G., and Q.X. are named as inventors on China patent application (no. 2024110168233), which is related to this work. Jinan Microecological Biomedicine Shandong Laboratory and Nanjing University are the applicants of this patent application. X.G. and Q.X. are employees of Jinan Microecological Biomedicine Shandong Laboratory. J.W. and C.J. are employees of Nanjing University., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction, a hallmark of immune cell failure, affects the antitumor effects of immune cells through metabolic reprogramming, fission, fusion, biogenesis, and immune checkpoint signal transduction of mitochondria. According to researchers, restoring damaged mitochondrial function can enhance the efficacy of immune cells. Nevertheless, the mechanism of mitochondrial dysfunction in immune cells in patients with cancer is unclear. In this review, we recapitulate the impact of mitochondrial dysfunction on the antitumor effects of T cells, natural killer cells, dendritic cells, and tumor-associated macrophage and propose that targeting mitochondria can provide new strategies for antitumor therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Yin, Huang, Zhang and Lu.)

Purpose: The infiltration of immune cells and their roles of the infiltrating-immune cells in gastrointestinal stromal tumor (GIST) is still unclear. We aimed to discover the infiltration cell types and the relationship between the infiltrating-immune cells and the progression of GIST., Experimental Design: Single-cell RNA sequencing were performed to discover types of the infiltrating-immune cells and to analyze CellChat between cells. Immunohistochemistry of 80 GIST samples were used to clarify the relation between macrophages and recurrence risk. In vitro , flow cytometry and Real-time PCR were performed to uncover a potential mechanism of tumor cell regulation of macrophages., Results: Tumor cells, macrophages, and T-cells were the predominant cell types. The MIF/CXCR4 axis was the most common ligand-receptor interaction between macrophages and tumor cells. As the risk increased, expression levels of CD68, CD206, MIF, and CXCR4 gradually increased. In vitro , we found that GIST882 was able to secrete MIF and GIST882 cell supernatant upregulated M2 polarization. Real-time PCR showed that expression levels of IL-10 mRNA and Arginase-1 mRNA were also the highest in the GIST882 cell supernatant group., Conclusions: These findings identify that macrophages are the most abundant infiltrating cells in GIST. The MIF/CXCR4 axis is the most common ligand-receptor interaction between macrophages and tumor cells. GIST cells can regulate macrophage M2 polarization through the MIF/CXCR4 axis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiao, Xu, Yang, Zhao, Xie, Lei and Wu.)

HBV infection is a key risk factor for the development and progression of hepatocellular carcinoma (HCC), a highly invasive tumor, and is characterized by its persistent immunosuppressive microenvironment. This review provides an in-depth analysis of HBV-related HCC and explores the interactions between neutrophils, natural killer cells, and dendritic cells, examining their roles in regulating tumor-associated macrophages and CD8+ T cells and shaping the tumor microenvironment. Two critical players in the immunosuppressive milieu of HBV-related HCC are CD8+ T cells and tumor-associated macrophages (TAMs). The study explores how TAMs, initially recruited to combat infection, transform, adopting a tumor-promoting phenotype, turning against the body, promoting tumor cell proliferation, suppressing anti-tumor immunity, and assisting in the spread of cancer. Meanwhile, CD8+ T cells, crucial for controlling HBV infection, become dysfunctional and exhausted in response to persistent chronic viral inflammation. The review then dissects how TAMs manipulate this immune response, further depleting CD8+ T cell functions through mechanisms like arginine deprivation and creating hypoxic environments that lead to exhaustion. Finally, it explores the challenges and promising therapeutic avenues that target TAMs and CD8+ T cells, either separately or in combination with antiviral therapy and personalized medicine approaches, offering hope for improved outcomes in HBV-related HCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Khan, Mao, Hu, Shi, Wang, Rehman and Li.)

Breast cancer is a significant global health issue. Tumor-associated macrophages (TAMs) are crucial in influencing the tumor microenvironment and the progression of the disease. TAMs exhibit remarkable plasticity in adopting distinct phenotypes ranging from pro-inflammatory and anti-tumorigenic (M1-like) to immunosuppressive and tumor-promoting (M2-like). This review elucidates the multifaceted roles of TAMs in driving breast tumor growth, angiogenesis, invasion, and metastatic dissemination. Significantly, it highlights the intricate crosstalk between TAMs and non-coding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, as a crucial regulatory mechanism modulating TAM polarization and functional dynamics that present potential therapeutic targets. Nanotechnology-based strategies are explored as a promising approach to reprogramming TAMs toward an anti-tumor phenotype. Various nanoparticle delivery systems have shown potential for modulating TAM polarization and inhibiting tumor-promoting effects. Notably, nanoparticles can deliver ncRNA therapeutics to TAMs, offering unique opportunities to modulate their polarization and activity.