The heterogeneity of tumor-associated macrophages and strategies to target it

Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.

Inhibition of M2 tumor-associated macrophages polarization by modulating the Wnt/β-catenin pathway as a possible liver cancer therapy method

The problem of liver cancer is becoming increasingly important due to the epi-demic of metabolic diseases and persistent high alcohol consumption.This deter-mines 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.

MicroRNA-206 as a promising epigenetic approach to modulate tumor-associated macrophages in hepatocellular carcinoma

This letter comments on the recently published manuscript by Huang et al in the World Journal of Gastroenterology,which focused on the immunomodulatory effect of Calculus bovis on hepatocellular carcinoma(HCC)tumor microenvironments(TME)by inhibiting M2-tumor-associated macrophage(M2-TAM)polarization via Wnt/β-catenin pathway modulation.Recent research highlights the crucial role of TAMs and their polarization towards the M2 phenotype in promoting HCC progression.Epigenetic regulation,particularly through microRNAs(miR),has emerged as a key factor in modulating immune responses and TAM polarization in the TME,influencing treatment responses and tumor progression.This editorial focuses on miR-206,which has been found to inhibit HCC cell proliferation and migration and promote apoptosis.Moreover,miR-206 enhances anti-tumor immune responses by promoting M1-polarization of Kupffer cells,facilitating CD8+T cell recruitment and suppressing liver cancer stem cell expansion.However,challenges remain in understanding the precise mechanisms regulating miR-206 and its potential as a therapeutic agent.Targeting epigenetic mechanisms and improving strategies,whether through pharmacological or genetic approaches,offer promising avenues to sensitize tumor cells to chemotherapy.Understanding the intricate interactions between cancer and non-coding RNA regulation opens new avenues for developing targeted therapies,potentially improving HCC prognosis.

Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer

The relevant mechanism of tumor-associated macrophages(TAMs)in the treatment of colorectal cancer patients with immune checkpoint inhibitors(ICIs)is discussed,and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies.As a class of drugs widely used in clinical tumor immunotherapy,ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system.The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly.The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs.ICIs can regulate the phenotypic function of TAMs,and TAMs can also affect the tolerance of colorectal cancer to ICI therapy.TAMs play an important role in ICI resistance,and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.

Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer

BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

Correlation of tumor-associated macrophage density and proportion of M2 subtypes with the pathological stage of colorectal cancer

BACKGROUND Colorectal cancer(CRC)is a prevalent global malignancy with complex prognostic factors.Tumor-associated macrophages(TAMs)have shown paradoxical associations with CRC survival,particularly concerning the M2 subset.AIM We aimed to establish a simplified protocol for quantifying M2-like TAMs and explore their correlation with clinicopathological factors.METHODS A cross-sectional study included histopathological assessment of paraffinembedded tissue blocks obtained from 43 CRC patients.Using CD68 and CD163 immunohistochemistry,we quantified TAMs in tumor stroma and front,focusing on M2 proportion.Demographic,histopathological,and clinical parameters were collected.RESULTS TAM density was significantly higher at the tumor front,with the M2 proportion three times greater in both zones.The tumor front had a higher M2 proportion,which correlated significantly with advanced tumor stage(P=0.04),pathological nodal involvement(P=0.04),and lymphovascular invasion(LVI,P=0.01).However,no significant association was found between the M2 proportion in the tumor stroma and clinicopathological factors.CONCLUSION Our study introduces a simplified protocol for quantifying M2-like TAMs in CRC tissue samples.We demonstrated a significant correlation between an increased M2 proportion at the tumor front and advanced tumor stage,nodal involvement,and LVI.This suggests that M2-like TAMs might serve as potential indicators of disease progression in CRC,warranting further investigation and potential clinical application.

Abnormally activated wingless/integrated signaling modulates tumor-associated macrophage polarization and potentially promotes hepatocarcinoma cell growth

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.

Role of tumor-associated macrophages in common digestive system malignant tumors

Many digestive system malignant tumors are characterized by high incidence and mortality rate.Increasing evidence has revealed that the tumor microenvironment(TME)is involved in cancer initiation and tumor progression.Tumor-associated macrophages(TAMs)are a predominant constituent of the TME,and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer.TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype.The latter especially are crucial drivers of tumor invasion,growth,angiogenesis,metastasis,immunosuppression,and resistance to therapy.TAMs are of importance in the occurrence,development,diagnosis,prognosis,and treatment of common digestive system malignant tumors.In this review,we summarize the role of TAMs in common digestive system malignant tumors,including esophageal,gastric,colorectal,pancreatic and liver cancers.How TAMs promote the development of tumors,and how they act as potential therapeutic targets and their clinical applications are also described.

Role of Cyclin D1b in Inducing Macrophages Toward a Tumor-associated Macrophage-like Phenotype in Murine Breast Cancer

Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TAM activators.Cyclin D1b is a highly oncogenic splice variant of cyclin D1.We previously reported that cyclin D1b enhances the invasiveness of breast cancer cells by inducing EMT.However,the role of cyclin D1b in inducing macrophage differentiation toward tumor-associated macrophage-like cells remains unknown.This study aimed to explore the relationship between breast cancer cells overexpressing cyclin Dlb and TAMs.Methods:Mouse breast cancer 4T1 cells were transfected with cyclin D1b variant and co-cultured with macrophage cells in a Transwell coculture system.The expression of characteristic cytokines in differentiated macrophages was detected using qRT-PCR,ELISA and zymography assay.Tumor-associated macrophage distribution in a transplanted tumor was detected by immunofluorescence staining.The proliferation and migration ability of breast cancer cells was detected using the cell counting kit-8(CCK-8)assay,wound healing assay,Transwell invasion assay,and lung metastasis assay.Expression levels of mRNAs were detected by qRT-PCR.Protein expression levels were detected by Western blotting.The integrated analyses of The Cancer Genome Atlas(TCGA)datasets and bioinformatics methods were adopted to discover gene expression,gene coexpression,and overall survival in patients with breast cancer.Results:After co-culture with breast cancer cells overexpressing cyclin D1b,RAW264.7 macrophages were differentiated into an M2 phenotype.Moreover,differentiated M2-like macrophages promoted the proliferation and migration of breast cancer cells in turn.Notably,these macrophages facilitated the migration of breast cancer cells in vivo.Further investigations indicated that differentiated M2-like macrophages induced EMT of breast cancer cells accompanied with upregulation of TGF-β1 and integrinβ3 expression.Conclusion:Breast cancer cells transfected with cyclin D1b can induce the differentiation of macrophages into a tumor-associated macrophage-like phenotype,which promotes tumor metastasis in vitro and in vivo.

Activation of Toll-like receptors signaling in non-small cell lung cancer cell line induced by tumor-associated macrophages

Background： Inflammation is often linked with the progress and poor outcome of lung cancer. The understanding of the relationship between tumor-associated macrophages （TAMs） and lung cancer cells involves in the underlying mechanism of inflammatory cytokine production. Toll-like receptors （TLRs） are engaged in promoting the production of pro-inflammatory cytokines and play an important role in tumor immunology. Methods： To investigate the mechanisms by which TAMs influence the production of pro-inflammatory cytoldnes in lung cancer cells, we established an in vitro coculture system using TAMs and human non- small cell lung cancer （NSCLC） cell line SPC-A1. Levels of interleukin （IL）-113, IL-6 and IL-8 in SPC-A1 were evaluated by RT-PCR and cytometric bead array assay after being cocultured with TAMs. Expression changes of TLRs and TLRs signaling pathway proteins in SPC-Al were further confirmed by RT-PCR and western blot. The level changes of IL-1β, IL-6 and IL-8 in SPC-Al were also detected after the stimulation of TLRs agonists. Results： We found that the phenotype markers of TAMs were highly expressed after stimulating human monocyte cell line THP-1 by phorbol-12-myristate-β-acetate （PMA）. Higher mRNA and supernate secretion levels of IL-1β, IL-6 and IL-8 were detected in SPC-A1 after being eocultured with TAMs. We also found that TLR1, TLR6 and TLR7 were up-regulated in SPC-A1 in the coculture system with TAMs. Meanwhile, TLRs signaling pathway proteins were also significantly activated. Moreover, pre-treatment with agonist ligands for TLR1, TLR6 and TLR7 could dramatically promote inductions of IL-1β, IL-6 and IL-8. Conclusions： These findings demonstrated that TAMs may enhance IL-1β, IL-6 and IL-8 expressions via TLRs signaling pathway. We conclude that TAMs contribute to maintain the inflammation microenvironment and ultimately promote the development and progression of lung cancer.

Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis

Objective: Recent studies have shown that tumor-associated macrophages(TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer(GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified.Methods: THP-1 monocytes were induced by PMA/interleukin(IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation(Ch IP) assay were used to investigate the mechanism of transforming growth factor β2(TGFβ2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo.Results: We found that Kindlin-2 expression was upregulated at both m RNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGFβ2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-кB. TAMs thus participated in the progression of GC through the TGFβ2/NF-κB/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo.Conclusions: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGFβ2/NF-κB/Kindlin-2 axis, providing a possibility for new treatment options and approaches.

Promotion of Sema4D expression by tumor-associated macrophages: Significance in gastric carcinoma

AIM To study the role of semaphorin 4 D(Sema4 D) expression promoted by tumor-associated macrophages(TAMs) in gastric carcinoma cells and its clinical significance in the invasion and metastasis of gastric carcinoma.METHODS CD68 and Sema4 D expression was analyzed in gastric carcinoma and adjacent normal tissues from 290 patients using the immunohistochemical streptavidinperoxidase method, and their relationships with clinicopathological features were evaluated. Human M2 macrophages were induced in vitro and co-cultured in non-contact with gastric carcinoma SGC-7901 cells. Changes in the secretory Sema4 D level in the SGC-7901 cell supernatant were measured using an enzymelinked immunosorbent assay. The effects of TAMs on SGC-7901 cell invasion and migration were assessed with invasion and migration assays, respectively.RESULTS CD68 and Sema4 D protein expression was significantly higher in gastric carcinoma tissues than in adjacent normal tissues(71.7% vs 33.8% and 74.5% vs 42.8%, respectively; P < 0.01). CD68 and Sema4 D protein expression was significantly associated with histological differentiation, TNM stage, and lymph node metastasis(P < 0.05), and their expression levels were positively correlated with one another(r = 0.467, P < 0.01). In the in vitro experiment, secretory Sema4 D protein expression was significantly increased in the supernatant of SGC-7901 cells co-cultured with TAMs compared with the blank control(1224.13 ± 29.43 vs 637.15 ± 33.84, P < 0.01). Cell invasion and metastasis were enhanced in the Transwell invasion and migration assays(P < 0.01).CONCLUSION TAMs promote the invasion and metastasis of gastric carcinoma cells possibly through upregulated secretory Sema4 D protein expression. Combined detection of TAM markers, CD68 and Sema4 D, in gastric carcinoma tissue shows potential to predict the trend of gastric carcinoma progression.

2-Hexyl-4-Pentylenic Acid(HPTA) Stimulates the Radiotherapy-induced Abscopal Effect on Distal Tumor through Polarization of Tumor-associated Macrophages

Objective The aim of this study was to explore the effects of 2-hexyl-4-pentylenic acid(HPTA)in combination with radiotherapy(RT)on distant unirradiated breast tumors.Methods Using a rat model of chemical carcinogen(7,12-dimethylbenz[a]anthracene,DMBA)-induced breast cancer,tumor volume was monitored and treatment response was evaluated by performing HE staining,immunohistochemistry,immunofluorescence,q RT-PCR,and western blot analyses.Results The results demonstrated that HPTA in combination with RT significantly delayed the growth of distant,unirradiated breast tumors.The mechanism of action included tumor-associated macrophage(TAM)infiltration into distant tumor tissues,M1 polarization,and inhibition of tumor angiogenesis by IFN-γ.Conclusion The results suggest that the combination of HPTA with RT has an abscopal effect on distant tumors via M1-polarized TAMs,and HPTA may be considered as a new therapeutic for amplifying the efficacy of local RT for non-targeted breast tumors.

Analysis of invasiveness and tumor-associated macrophages infiltration in solid pseudopapillary tumors of pancreas

BACKGROUND Solid pseudopapillary tumor(SPT)is a rare pancreatic tumor.Considering its malignant behaviors,SPT has been classified as a low-grade malignant tumor.Indeed,only 9.2%of all SPT patients are initially diagnosed as malignant with invasion or metastasis.Thus,one of the challenges in managing SPT patients is predicting malignant behavior.AIM To investigate the malignant behavior and tumor-associated macrophage(TAM)infiltration between different histopathologic features of SPT patients.METHODS Twenty-five formalin-fixed paraffin-embedded tissue samples from 22 patients pathologically diagnosed with an SPT between 2009 and 2019 at West China Hospital were included in this retrospective study.Integrity of the capsule and growth pattern of the tumor cells was assessed microscopically in hematoxylineosin(HE)-stained sections.Based on the histopathological features,the SPT patients were divided into two groups:capsule or invasion.Clinical features,malignant behavior,and TAM infiltration were compared between the two groups.RESULTS Among the 22 SPT patients,11 were identified for each group,having either a capsule or invasion histopathologic feature.Malignant behavior was more frequent in the invasion group,including 2 patients who had peripheral organ invasion,3 with liver metastasis,and 1 with both lymph node and spleen metastases(P=0.045).Ki-67 index of more than 3%was also more frequent in the invasion group(P=0.045).Immunohistochemical analysis showed that the invasion group had a significant increase of CD68-positive TAMs in intratumor and peritumor sites in comparison with the capsule group(all P<0.0001).Similarly,CD163-positive M2-like macrophages were also markedly increased in the intratumor and peritumor sites in the invasion group(all P<0.0001).At the liver metastasis site,both intratumor and peritumor tissues showed relatively high-level CD68-positive TAMs and CD163-positive M2-like macrophages infiltration.However,the differences between the intratumor,peritumor and normal hepatic tissues did not reach statistical significance(all P>0.05).CONCLUSION SPT patients with invasion evident under microscope were more likely to exhibit malignant behavior and TAM infiltration,especially M2-like macrophages.This finding can help in future investigations of the underlying mechanism of TAM-mediated SPT malignant behavior.

Progress of tumor-associated macrophages in pancreatic cancer

Pancreatic cancer is a kind of highly aggressive malignant tumor of the digestive system.The treatment of local tumors is mainly surgical resection,but the indications are too harsh.For advanced pancreatic cancer,chemotherapy is the standard treatment,but patients have severe side effects and develop drug resistance.Tumor-associated macrophages in the tumor microenvironment of pancreatic cancer are the most abundant immune cells and play a very important role in tumor development and chemoresistance.Antitumor-associated macrophage therapy has shown some therapeutic potential.Therefore,this article reviews the mechanism of tumor-associated macrophages in pancreatic cancer and the progress of tumor-associated macrophage targeted therapy.

肿瘤相关巨噬细胞(TAMs):从基础到临床

巨噬细胞是肿瘤微环境(TME)的重要组成,对肿瘤的发生发展至关重要。免疫系统对癌前突变细胞进行免疫监视,抑制肿瘤发生发展,巨噬细胞在其中发挥不可或缺的功能。然而,大量证据表明肿瘤相关巨噬细胞(TAMs)在肿瘤进展过程中发生功能转换,变成有利于肿瘤的免疫抑制状态,促进肿瘤免疫逃逸。很多研究尝试通过不同方法理清巨噬细胞功能转换的机制,同时运用这些机制探索靶向TAMs的癌症免疫治疗新策略。本文将阐述巨噬细胞分类方法的演变,结合临床信息介绍靶向TAMs的癌症免疫疗法的新进展。

Reprogramming tumor-associated macrophages and inhibiting tumor neovascularization by targeting MANF-HSF1-HSP70-1 pathway:An effective treatment for hepatocellular carcinoma

In advanced hepatocellular carcinoma(HCC)tissues,M2-like tumor-associated macrophages(TAMs)are in the majority and promotes HCC progression.Contrary to the pro-tumor effect of M2-like TAMs,M1-like TAMs account for a small proportion and have anti-tumor effects.Since TAMs can switch from one type to another,reprogramming TAMs may be an important treatment for HCC therapy.However,the mechanisms of phenotypic switch and reprogramming TAMs are still obscure.In this study,we analyzed differential genes in normal macrophages and TAMs,and found that loss of MANF in TAMs accompanied by high levels of downstream genes negatively regulated by MANF.MANF reprogrammed TAMs into M1 phenotype.Meanwhile,loss of MANF promoted HCC progression in HCC patients and mice HCC model,especially tumor neovascularization.Additionally,macrophages with MANF supplement suppressed HCC progression in mice,suggesting MANF supplement in macrophage was an effective treatment for HCC.Mechanistically,MANF enhanced the HSF1-HSP70-1 interaction,restricted HSF1 in the cytoplasm of macrophages,and decreased both mRNA and protein levels of HSP70-1,which in turn led to reprogramming TAMs,and suppressing neovascularization of HCC.Our study contributes to the exploration the mechanism of TAMs reprogramming,which may provide insights for future therapeutic exploitation of HCC neovascularization.

Nanomaterials modulate tumor-associated macrophages for the treatment of digestive system tumors

The treatment of digestive system tumors presents challenges,particularly in immunotherapy,owing to the advanced immune tolerance of the digestive system.Nanomaterials have emerged as a promising approach for addressing these challenges.They provide targeted drug delivery,enhanced permeability,high bioavailability,and low toxicity.Additionally,nanomaterials target immunosuppressive cells and reshape the tumor immune microenvironment(TIME).Among the various cells in the TIME,tumor-associated macrophages(TAMs)are the most abundant and play a crucial role in tumor progression.Therefore,investigating the modulation of TAMs by nanomaterials for the treatment of digestive system tumors is of great significance.Here,we present a comprehensive review of the utilization of nanomaterials to modulate TAMs for the treatment of gastric cancer,colorectal cancer,hepatocellular carcinoma,and pancreatic cancer.We also investigated the underlying mechanisms by which nanomaterials modulate TAMs to treat tumors in the digestive system.Furthermore,this review summarizes the role of macrophage-derived nanomaterials in the treatment of digestive system tumors.Overall,this research offers valuable insights into the development of nanomaterials tailored for the treatment of digestive system tumors.

Fu-Zheng-Yi-Liu Formula inhibits the stem cells and metastasis of prostate cancer via tumor-associated macrophages/C-C motif chemokine ligand 5 pathway in tumor microenvironment

Prostate cancer(PCa)is the second most common malignancy among men globally.The Fu-Zheng-Yi-Liu(FZYL)Formula has been widely utilized in the treatment of PCa.This study investigates whether the FZYL Formula can inhibit PCa by tar-geting the TAMs/CCL5 pathway.We conducted in vitro co-cultures and in vivo co-injections of PCa cells and TAMs to mimic their in-teraction.Results showed that the FZYL Formula significantly reduced the proliferation,colony formation,subpopulations of PCSCs,and sphere-formation efficacy of PCa cells,even in the presence of TAM co-culture.Additionally,the Formula markedly decreased the migration,invasion,and epithelial-mesenchymal transition(EMT)of PCa cells induced by TAMs.The FZYL Formula also reversed M2 phenotype polarization in TAMs and dose-dependently reduced their CCL5 expression and secretion,with minimal cytotoxicity observed.Mechanistic studies confirmed that the TAMs/CCL5 axis is a critical target of the FZYL Formula,as the addition of exogen-ous CCL5 partially reversed the formula’s inhibitory effects on PCSCs self-renewal in the co-culture system.Importantly,the Formula also significantly inhibited the growth of PCa xenografts,bone metastasis,and PCSCs activity in vivo by targeting the TAMs/CCL5 pathway.Overall,this study not only elucidates the immunomodulatory mechanism of the FZYL Formula in PCa therapy but also highlights the TAMs/CCL5 axis as a promising therapeutic target.

Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages throughα-ketoglutarate and mTORC1 signaling

Phosphoglycerate dehydrogenase(PHGDH)has emerged as a crucial factor in macromolecule synthesis,neutralizing oxidative stress,and regulating methylation reactions in cancer cells,lymphocytes,and endothelial cells.However,the role of PHGDH in tumor-associated macrophages(TAMs)is poorly understood.Here,we found that the T helper 2(Th2)cytokine interleukin-4 and tumor-conditioned media upregulate the expression of PHGDH in macrophages and promote immunosuppressive M2 macrophage activation and proliferation.Loss of PHGDH disrupts cellular metabolism and mitochondrial respiration,which are essential for immunosuppressive macrophages.Mechanistically,PHGDH-mediated serine biosynthesis promotesα-ketoglutarate production,which activates mTORC1 signaling and contributes to the maintenance of an M2-like macrophage phenotype in the tumor microenvironment.Genetic ablation of PHGDH in macrophages from tumor-bearing mice results in attenuated tumor growth,reduced TAM infiltration,a phenotypic shift of M2-like TAMs toward an M1-like phenotype,downregulated PD-L1 expression and enhanced antitumor T-cell immunity.Our study provides a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and hinder tumor progression.