Cancer immunology research最新文献

{"title":"Ex Vivo Expansion of Melanoma Tumor-Infiltrating Lymphocytes Leads to a Dominant Exhausted T-cell Population with a Lack of Memory Markers.","authors":"Gianfilippo Coppola, Samuel Kerr, Pei-Chun Cha, Alexey Bersenev, Kelly Olino, Harriet M Kluger, Mario Sznol, Sarah A Weiss, Marcus W Bosenberg, Steven H Kleinstein, Diane S Krause, Michael E Hurwitz, Samuel G Katz","doi":"10.1158/2326-6066.CIR-25-0798","DOIUrl":"10.1158/2326-6066.CIR-25-0798","url":null,"abstract":"<p><p>Tumor-infiltrating lymphocytes (TIL) can be isolated from patient tumors, greatly expanded ex vivo, and returned to the patient for therapeutic effect. Recent clinical trials have highlighted the efficacy of TILs for a subset of patients and supported FDA approval for melanoma. How TILs evolve during the manufacturing process is still unknown and likely critical to improving the therapy for more patients. To characterize cell modification during TIL expansion, we performed single-cell RNA and T-cell receptor sequencing of TILs isolated from patient tumors and their paired ex vivo expanded cell products. We found large transcriptional differences between pre- and post-expansion TILs. Post-expansion TILs were predominantly exhausted and lacked naïve or memory cell phenotypes, including a decreased percentage of CD39/CD69 double-negative (DN) \"stem-like\" T cells. Coactivating receptors CD137 and CD27 decreased, whereas CD30 increased. Among coinhibitory receptors, PDCD1 (PD-1) decreased, whereas HAVCR2 (TIM3) and LAG3 showed the largest increases with expansion. Other gene families that showed large increases with ex vivo growth included cytotoxicity- and APC-associated genes. Individual clonotypes were distributed among multiple cell differentiation states, which exhibited high degrees of plasticity during expansion. Although ex vivo expanded TILs are predominantly terminally differentiated, exhausted, and transcriptionally highly distinct from the initial TILs, there is also a large progenitor exhausted CD8 T-cell population, and DN numbers increase. Future work to amplify subpopulations of TILs with memory cell phenotypes, such as the DN cells, will likely further improve this therapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"861-874"},"PeriodicalIF":8.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13032746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146178074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Constitutive STAT3 Signaling, in Comparison with STAT5, Enhances CAR T-cell Efficacy and Lowers Systemic Toxicity.","authors":"Haosong Zhang, Yusuke Ito, Hitomi Kasuya, Taeko Hayakawa, Yang Li, Satoshi Inoue, Tsunenori Ouchida, Yuki Kagoya","doi":"10.1158/2326-6066.CIR-25-0611","DOIUrl":"10.1158/2326-6066.CIR-25-0611","url":null,"abstract":"<p><p>Providing cytokine signaling is a key strategy to boost the efficacy of chimeric antigen receptor (CAR) T-cell therapy. However, the individual roles of key downstream mediators, STAT3 and STAT5, remain incompletely understood. In this study, we engineered CAR T cells to express constitutively active mutants of STAT3 (Y640F; caSTAT3) and STAT5 (N642H; caSTAT5) to investigate their individual functions. In vitro, caSTAT3 CAR T cells exhibited enhanced effector function and a robust memory phenotype, with broader transcriptional changes involving both effector- and memory-associated genes compared with caSTAT5 CAR T cells. However, caSTAT3 CAR T cells failed to expand because of activation of apoptosis-related gene programs. In contrast, caSTAT5 CAR T cells demonstrated sustained proliferation over time. Despite the limited in vitro expansion, caSTAT3 CAR T cells exhibited reduced transgene toxicity in vivo and exerted durable antitumor activity in both leukemia and solid tumor models without significant off-tumor toxicity. Titrated expression of caSTAT3 maintained enhanced effector function without inducing apoptosis. On the other hand, caSTAT5 CAR T cells efficiently accumulated in tumors but also infiltrated nontumor tissues, causing lethal systemic toxicity. Co-expression of caSTAT3 and caSTAT5 markedly enhanced the long-term proliferative capacity of CAR T cells, even in the absence of antigen stimulation or cytokine supplementation. These findings elucidate the distinct impacts of STAT3 and STAT5 activation on CAR T-cell behavior and suggest that selective activation of STAT3 at optimal levels may improve CAR T-cell efficacy while minimizing off-tumor toxicities.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"845-860"},"PeriodicalIF":8.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147316181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B Cells and Tertiary Lymphoid Structures as Integral Components of the Cancer Immunity Cycle.","authors":"Dimitrios N Sidiropoulos, Won Jin Ho","doi":"10.1158/2326-6066.CIR-26-0311","DOIUrl":"10.1158/2326-6066.CIR-26-0311","url":null,"abstract":"<p><p>The influence B cells have in the tumor microenvironment has historically remained unresolved across solid tumors. At the same time, numerous findings of ectopic germinal centers in inflamed tumors containing tertiary lymphoid structures have been the impetus for redefining what effective antitumor immunity looks like. In this issue, Zeng and colleagues and Rodriguez Chevez and colleagues enrich our perspective on the roles of intratumoral B cells and their cross-talk with T cells intratumorally to augment adaptive immune responses targeting tumor antigens. See related article by Zeng et al., p. 771 See related article by Rodriguez Chevez et al., p. 792.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"716-717"},"PeriodicalIF":8.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response of B Cells Specific for Polyomavirus-Derived Oncoprotein Is Predictive of Merkel Cell Carcinoma Tumor Control.","authors":"Haroldo J Rodriguez Chevez, Allison J Remington, Matthew D Gray, Rian Alam, Macy W Gilmour, Carina Morningstar, Gabriel F Alencar, Thomas Pulliam, Erin M McClure, Neha Singh, Francesca Urselli, Scotia Ouellette, Katrina Poljakov, Kimberly S Smythe, Rima M Kulikauskas, Kristin L Robinson, Ata S Moshiri, Cecilia C S Yeung, MingGang Lin, Kristen R Shimp, Allison Schwartz, Anne M Macy, Marti R Tooley, Melissa L Baker, Joseph J Carter, Kayla Hopwo, Naina Singhi, Jakob Bakhtiari, Mikel Ruterbusch, Carolyn Shasha, Maria Iuliano, Logan J Mullen, Blair L DeBuysscher, Joshua R Veatch, David M Koelle, Denise A Galloway, Paul Nghiem, Justin J Taylor","doi":"10.1158/2326-6066.CIR-25-0950","DOIUrl":"10.1158/2326-6066.CIR-25-0950","url":null,"abstract":"<p><p>Merkel cell carcinomas (MCC) typically arise from the clonal integration of the Merkel cell polyomavirus. Immunogenic viral oncoproteins then lead to tumorigenesis. Oncoprotein-specific T cells are essential for anti-MCC immunity, but it is unclear whether B cells promote tumor control. In this study, we analyzed the frequency and phenotype of viral oncoprotein-specific and total B cells in blood samples from 47 patients with MCC and tumor samples from another 19 patients with MCC. The phenotype of blood B cells did not correlate with the outcomes of patients with MCC. In contrast, all 11 patients with robust oncoprotein-specific antibody-secreting and/or germinal center B cells in tumors experienced long-term MCC control. In vitro, B cells engineered to be specific for viral oncoproteins increased the sensitivity of oncoprotein-specific CD4+ T cells by more than 50-fold. Together, our findings suggest that cancer-specific B cells promote antitumor immunity via increased responses by T cells and that cancer-specific augmentation of B cells could be therapeutically relevant. See related Spotlight, p. 716.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"792-810"},"PeriodicalIF":8.2,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13074713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147353732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer cell-intrinsic SSBP4 enables tumor immune evasion by promoting cholesterol biosynthesis.","authors":"Peiqi Ou, Ittai Eres, Junjie Zhao, Chia-Jung Han, Jaehak Oh, Aeryon Kim, Jiayi Dong, Hong Zhou, Tracy Yamawaki, Chi-Ming Li, Andrew Rankin, Rajkumar Noubade, Xin Yu","doi":"10.1158/2326-6066.CIR-25-1312","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1312","url":null,"abstract":"<p><p>The immunosuppressive tumor microenvironment (TME) contributes to resistance against checkpoint inhibitors. However, the precise factors that shape the immune contexture of the TME remain elusive. Here, we report that Single-Stranded DNA Binding Protein 4 (SSBP4), a previously uncharacterized protein, suppresses intratumoral T-cell activation by promoting excessive cholesteryl ester production in tumor cells. Overexpression of SSBP4 in tumor cells decreased T-cell infiltration and accelerated tumor growth in murine syngeneic tumor models. Conversely, genetic ablation of SSBP4 in tumor cells enhanced T-cell infiltration and inhibited tumor growth in a CD8+ T cell-dependent manner. Mechanistically, SSBP4 upregulated cholesterol synthesis genes, leading to increased production of cholesterol and cholesteryl esters in tumor cells, which directly suppressed CD8+ T-cell activation and function. Furthermore, SSBP4 abrogation significantly improved the efficacy of anti-PD-1 treatment. Thus, in this study, we have identified SSBP4 as a cancer cell-intrinsic regulator of cholesterol metabolism that contributes to tumor immune evasion.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor-derived complement C3 overexpression in STK11-mutant lung adenocarcinoma drives tumor growth and immune checkpoint inhibitor resistance.","authors":"Sora Suzuki, Bojidar Kandar, Catrina Ting, Peter Deraska, Te-An Chen, Thejaswini Giridharan, Anm Nazmul H Khan, Kristopher Attwood, Han Yu, Kayla Catalfamo, Prashant K Singh, Ryan T Bushey, Elizabeth B Gottlin, Michael J Campa, Edward F Patz, Daniel Ajona, Ruben Pio, Brahm H Segal, Edwin H Yau","doi":"10.1158/2326-6066.CIR-25-0534","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0534","url":null,"abstract":"<p><p>Loss-of-function STK11 mutations occur in 15-20% of lung adenocarcinomas (LUAD) and correlate with immunotherapy failure and worse survival. By integrating analysis of human tumor samples, a human LUAD cell line panel, and CCLE and TCGA datasets, we found that C3 production was increased in human STK11-mutant versus STK11-wildtype LUAD, modulated by LKB1 loss, while high C3 expression in STK11-mutant LUAD was associated with worse survival. STK11-KO in syngeneic murine LUAD tumors resulted in increased neutrophil and reduced T cell infiltration and anti-PD-1 resistance. STK11-KO tumor growth was similar in C3-/- versus wildtype mice. In contrast, C3 deletion in STK11-KO tumors resulted in dramatic inhibition of tumor growth and enhanced sensitivity to anti-PD-1 in immunocompetent mice but had no significant effect in CD8-depleted wildtype mice or in nude mice, pointing to tumor-derived C3 promoting immune evasion. Mechanistically, STK11 loss drove tumor-derived C3 production and downstream CXCL2 and complement factor H (CFH) production that promoted immune evasion and impaired anti-PD-1 efficacy. Our results show a C3-driven signaling axis for STK11-mutant LUAD promoting immune evasion and identifies therapeutic targets to render these tumors sensitive to anti-PD-1.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An ICAM1-targeting chimeric costimulatory receptor mimics the immune synapse and enhances tumor-specific T cell function.","authors":"Irene M Min, Yanping Yang, Dessislava Stefanova, Yogindra Vedvyas, Diella S Babu, Dong-Hyun Lee, Yago Alcaina, Maria Cristina Riascos, Janusz Puc, Kevin J Chen, Juan Gonzalez-Valdivieso, Jose Thaiparambil, Maneeza Bilal, Bing He, Aidan C Burnett, Rasa Zarnegar, Thomas J Fahey, Moonsoo M Jin","doi":"10.1158/2326-6066.CIR-25-0529","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0529","url":null,"abstract":"<p><p>Engineered T cell therapies, such as chimeric antigen receptor (CAR) and T cell receptor (TCR)-based approaches, have transformed outcomes in hematological malignancies, yet their efficacy in solid tumors remains limited by tumor antigen escape, immunosuppressive microenvironments, and insufficient activation of CAR or TCR signaling. To overcome these barriers, we developed an intercellular adhesion molecule 1 (ICAM1)-specific chimeric costimulatory receptor (ICCR) engineered for expression in T cells to augment their activation. ICAM1 is broadly expressed across solid tumors and is further upregulated by IFNγ released during early T cell engagement, creating a feed-forward loop that reinforces tumor recognition. ICCR engagement with ICAM1 triggered NFκB signaling independently of TCR-p/MHC engagement; however, full T cell activation and cytotoxic function remained dependent on intact TCR signaling. In primary T cells, ICCR increased proliferation, cytokine production, and cytotoxicity, resulting in improved tumor control in two anaplastic thyroid cancer xenograft models treated with allogeneic or autologous ICCR-T cells. Mechanistically, ICCR strengthened tumor cell engagement, promoted selection and expansion of tumor-specific TCR clonotypes, and amplified downstream signaling pathways. These findings identify ICCR as a strategy that leverages an immune synapse-mimetic mechanism to enhance the function of low-activity tumor-specific TCRs and improve T cell responses in solid tumor microenvironments.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lenvatinib combined with PD-1 blockade therapy benefits gastric cancers through immunosuppressive macrophage modulation.","authors":"Nina Yi-Tzu Lin, Hirotomo Machiyama, Akihito Kawazoe, Atsuo Sai, Takuma Irie, Takumi Habu, Shota Fukuoka, Atsushi Kumanogoh, Naoya Sakamoto, Genichiro Ishii, Takahiro Kinoshita, Kohei Shitara, Hiroyoshi Nishikawa, Shohei Koyama","doi":"10.1158/2326-6066.CIR-25-0982","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0982","url":null,"abstract":"<p><p>The combination of multikinase inhibitors with PD-1 blockade therapy has emerged as a promising strategy to overcome resistance to PD-1 blockade monotherapy across multiple cancer types, including gastric cancer (GC). Here, we report that the multikinase inhibitor lenvatinib selectively reduced the number of CD206+CD163+ immunosuppressive macrophages in the tumor microenvironment (TME) and increased antitumor immunity. Longitudinal immunoprofiling was conducted with paired (pre- and posttreatment) tumor samples from patients with advanced GC who received first- or second-line combination therapy with lenvatinib and pembrolizumab in the EPOC1706 clinical trial. Patients with abundant CD206+CD163+ immunosuppressive macrophage infiltration exhibited favorable responses to combination therapy, accompanied by a significant posttreatment reduction in these cells. While this immunosuppressive macrophage infiltration was associated with resistance to PD-1 blockade monotherapy, it predicted a response to combination treatment: eight of the 9 patients with >440 CD206+CD163+ immunosuppressive macrophages/mm² responded, whereas none of the 8 patients who received monotherapy responded. Mechanistically, lenvatinib inhibited PDGFRα (platelet-derived growth factor receptor α)/FGFR (fibroblast growth factor receptor)-dependent p38 MAPK (mitogen-activated protein kinase) and AKT signaling pathways in F4/80highCD11bint immunosuppressive macrophages, triggering endoplasmic reticulum stress and an unresolved unfolded protein response, resulting 4 in their apoptosis. Furthermore, in multiple animal models, the therapeutic efficacy of the combination was observed in tumors with abundant immunosuppressive macrophages with activated PDGFR/FGFR-AKT/p38 MAPK signaling. Therefore, we propose that the abundance of immunosuppressive macrophages in the TME could serve as a predictive biomarker for patient stratification to guide rational anti-PD-1-based combination therapy in GC, enabling mechanism-based combination cancer immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NMB+ CXCL13+ CD4+ T cells -derived neuromedin-B promotes neuropeptide S receptor 1 positive malignant cells senescence and malignancy.","authors":"Mingke Yu, Lianhui Duan, Yulin Huang, Yixin Cheng, Yuting Wang, Guanyin Huang, Jingru Lian, Siqi Chen, Feiqiu Wen, Ling Guo, Xin Hong, Sangyu Shen, Guiping Chen, Yuanhong Gao, Chun Wu, Xuefei Liu","doi":"10.1158/2326-6066.CIR-25-1081","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1081","url":null,"abstract":"<p><p>Colorectal cancer (CRC) with liver metastases (CRCLM) remains a clinical challenge. CXCL13 is widely recognized as a biomarker of immunotherapy response. However, the functional heterogeneity (protumor vs. antitumor) of CXCL13⁺CD4⁺ T cell subsets has long been controversial. Through integrated analysis of single-cell RNA sequencing data from CRC clinical samples and pan-cancer datasets, combined with experimental validations, we first identified a pro-metastatic NMB⁺CXCL13⁺CD4⁺ T cell subset and uncovered a mechanism by which this subset regulates tumor cell \"senescence-malignant transition\", the NMB-NPSR1 axis. These NMB⁺CXCL13⁺CD4⁺ T cells induced senescence in NPSR1⁺ malignant cells via NMB secretion, leading to enhanced invasiveness and migration despite reduced proliferation. Activation of NPSR1 triggered the Wnt signaling pathway and Epithelial-Mesenchymal Transition (EMT), thereby enhancing cellular malignancy. This NPSR1+ senescent subpopulation also recruited endothelial cells and disrupted tight junction integrity, fostering a pro-metastatic microenvironment. As a proof-of-principle study, combination of the NPSR1 inhibitor SHA68 and anti-PD1 demonstrated remarkable antitumor effects using mouse models of CRC metastasis. Overall, this study uncovered the role of NMB+ CXCL13+ CD4+ T cells in promoting tumor cell senescence while influencing tumor metastasis, offering potential clinical implications for the diagnosis and treatment of metastatic CRC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low inflammation correlates with protumor Tim4+TREM1+ resident macrophage expansion and limited monocyte-derived macrophage differentiation during peritoneal colorectal cancer.","authors":"Margarita Ferriz, Natalia Alvarez-Ladrón, Alejandra Gutiérrez-González, Marta H Fernández-Sesma, Adrián Vega-Pérez, Juan Carlos Oliveros, Ana Cayuela López, Eduard Batlle, Daniele V Tauriello, Alejandro Prados, Carlos Ardavín","doi":"10.1158/2326-6066.CIR-25-0388","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0388","url":null,"abstract":"<p><p>Accumulating evidence indicates that peritoneal macrophages, comprising resident peritoneal macrophages (resMØs) and monocyte-derived non-resident macrophages (moMØs), contribute to peritoneal tumor progression, by promoting tumor cell proliferation and migration, and driving immunosuppression. However, the mechanisms governing the expansion of resMØs and moMØs, as well as their differential contributions to the peritoneal macrophage pool in tumor‑bearing mice and to tumor growth, remain to be elucidated. Using a mouse model of colorectal cancer (CRC) peritoneal metastasis, induced by intraperitoneal injection of tumor organoids derived from primary tumors in genetically engineered mice carrying Apc, Kras, Tgfbr2, and Trp53 mutations, and recapitulating human‑like metastatic CRC, we investigated the origin, expansion, and function of peritoneal macrophages during metastatic tumor growth. Our data support that the low inflammatory status of the peritoneal cavity during CRC peritoneal tumor growth restrains monocyte recruitment and the formation of Tim4⁻ resMØs and moMØs, while enabling a marked, proliferation‑driven expansion of Tim4⁺ resMØs. Tumor‑induced Tim4⁺ resMØs displayed a migratory and protumor transcriptomic signature, characterized by the activation of genes encoding key pro‑tumorigenic molecules and potential immunotherapeutic targets, including A2A/A2B, ARG1, IDO, IRG1, MMP12, PD-L1/2, SPP1, TREM1 or VEGF. Correspondingly, during peritoneal CRC tumor growth, Tim4⁺ TREM1⁺ resMØs migrated to the omentum, the principal peritoneal target organ for metastasis, and promoted CRC peritoneal tumor progression. These findings may contribute to the development of immunotherapies for CRC peritoneal metastasis that target tumor‑associated peritoneal macrophages.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}