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.

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.

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.

Anti-tumor efficacy of Calculus bovis: Suppressing liver cancer by targeting tumor-associated macrophages

Despite significant advances in our understanding of the molecular pathogenesis of liver cancer and the availability of novel pharmacotherapies,liver cancer remains the fourth leading cause of cancer-related mortality worldwide.Tumor relapse,resistance to current anti-cancer drugs,metastasis,and organ toxicity are the major challenges that prevent considerable improvements in patient survival and quality of life.Calculus bovis(CB),an ancient Chinese medicinal drug,has been used to treat various pathologies,including stroke,convulsion,epilepsy,pain,and cancer.In this editorial,we discuss the research findings recently published by Huang et al on the therapeutic effects of CB in inhibiting the development of liver cancer.Utilizing the comprehensive transcriptomic analyses,in vitro experiments,and in vivo studies,the authors demonstrated that CB treatment inhibits the tumor-promoting M2 phenotype of tumor-associated macrophages via downregulating Wnt pathway.While multiple studies have been performed to explore the molecular mechanisms regulated by CB,this study uniquely shows its role in modulating the M2 phenotype of macrophages present within the tumor microenvironment.This study opens new avenues of future investigations aimed at investigating this drug’s efficacy in various mouse models including the effects of combination therapy,and against drug-resistant tumors.

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.

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.

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.

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.

STAT3 activation of tumor-associated macrophages is associated with cytokines of tumor microenvironment and prognostic factors in breast cancer

Objective:The aim of this study was to investigate the correlation of STAT3 activation of tumor-associated macrophages(TAMs) and local cytokines(IL-1β,TNF-α,TGF-β and IL-12) and prognostic factors in breast cancer.Methods:TAMs in 50 primary breast cancers and macrophages in 15 normal breasts were examined by immunohistochemistry.And STAT3 DNA-binding activity of TAMs in 33/50 primary breast cancers was measured by transcription factor DNA-binding ELISA.In addition,the concentrations of IL-1β,TNF-α,TGF-β and IL-12 were measured in the 33 primary breast cancers extracts by ELISA.The correlation between STAT3 activity of TAMs and concentrations of IL-1β,TNF-α,TGF-β and IL-12 were analyzed.The correlation between STAT3 activity of TAMs and conventional clinicopathologic parameters were also evaluated.Results:The macrophages density showed a significant increase in primary breast cancers compared to normal breasts.STAT3 DNA-binding activity of TAMs in breast cancer was significantly higher than that of monocytes/macrophages from peripheral blood of the patients.Furthermore,STAT3 activity of TAMs was correlated significantly with the levels of IL-1β,TNF-α and TGF-β in breast cancer tissues.But an inverse association was observed between STAT3 activity of TAMs and IL-12.In addition,STAT3 activity of TAMs was higher in high histological type than in low histological type,and STAT3 activity of TAMs was higher in CerBb-2 positive than CerBb-2 negative.Conclusion:STAT3 activation of TAMs may be associate with increasing of IL-1β,TNF-α and TGF-β and decreasing of IL-12 in breast cancer.STAT3 activation of TAMs may also be correlated with histological grade and CerBb-2 status of breast cancer.

Tumor-associated macrophages, exosomes and tumor metastasis: a mini-review

Tumor invasion and metastasis is the primary cause of death in patients with malignant tumors.Tumor-associated macrophages are macrophages that infiltrate the tumor tissue,and are the most frequent immune cells in the tumor microenvironment.The macrophages could secrete a variety of cytokines and can recognize,identify and clear the tumor cells.As the tumor develops,it plays a vital role in the growth,invasion and metastasis of the cancer.However,the underline mechanisms of how the tumor-associated macrophages promoting tumor metastasis is still not fully understood.Present studies demonstrated that macrophage-related exosomes might play an essential role in tumor metastasis.Exosomes may provide potential targets for the prevention and treatment of macrophage-related tumor metastasis.

Remodeling tumor-associated macrophages in the tumor microenvironment

Tumor-associated macrophages(TAMs)actively interact with the tumor microenvironment(TME).The dynamic communication between TAMs and the TME is closely associated with tumorigenesis,progression,metastasis,and drug resistance.With the development of single-cell sequencing,specific TAMs have been identified,and their roles in the TME were explored.With the development of an under-standing of the interactions between TAMs and the TME,targeting TAMs has become a new treatment strategy for cancer therapy be-cause of their high plasticity.In this review,we highlight strategies for remodeling TAMs based on targeting specific genes involved in reg-ulating TAM phenotypes,blocking the crosstalk between TAMs and the TME,and targeting abnormal metabolic pathways.Moreover,we provided perspectives on the translational potential of targeting TAMs for cancer treatment,which could shed light on TAM-based thera-peutic strategy in the future.

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.

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.

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.

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.

The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype,promoting a favorable response to anti-PD-1 therapy via NLRP3 activation

The main challenges in the use of immune checkpoint inhibitors(ICIs)are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+T cells.Transforming the tumor microenvironment(TME)from“cold”to“hot”and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment.We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+mouse models.Using single-cell RNA sequencing,we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion,restoring T-cell function and promoting a favorable immunotherapy response.Mechanistically,we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling,thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production.As a result,APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment,thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity.Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86,p-NF-κB p65 and NLRP3 levels,accompanied by lower CD206 expression on macrophages.Collectively,these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.