Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Soluble TIM-3, likely produced by myeloid cells, predicts resistance to immune checkpoint inhibitors in metastatic clear cell renal cell carcinoma.","authors":"Ivan Pourmir, Nadine Benhamouda, Thi Tran, Hugo Roux, Joséphine Pineau, Alain Gey, Andyara Munoz, Nesrine Mabrouk, Nicolas Epaillard, Virginie Verkarre, Yann-Alexandre Vano, Eric Tartour, Stéphane Oudard","doi":"10.1186/s13046-025-03293-y","DOIUrl":"10.1186/s13046-025-03293-y","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapies targeting PD-1 and CTLA-4 are key components of the treatment of metastatic clear cell renal cell carcinoma (mccRCC). However, they have distinct safety profiles and resistance to treatment can occur. We assess soluble TIM-3 (sTIM-3) in the plasma of mccRCC patients as a potential theranostic biomarker, as well as its source and biological significance.</p><p><strong>Methods: </strong>We analyzed the association between sTIM-3 and overall survival (OS), tumor response, and common clinical and biological factors in two mccRCC cohorts treated with anti-PD-1 (nivolumab, n = 27), anti-PD-1 or anti-PD-1 + anti-CTLA-4 (nivolumab + ipilimumab - N + I, n = 124). The origin and role of sTIM-3 are studied on tumor and blood samples, using multiplex immunohistochemistry and flow cytometry, as well as analyses of publicly available single-cell transcriptomic (scRNAseq) and mass cytometry data.</p><p><strong>Results: </strong>sTIM-3 is significantly elevated in the plasma of treatment-naive mccRCC. It shows distinct associations with survival on anti-PD-1 vs anti-PD-1 + anti-CTLA-4: under nivolumab monotherapy, sTIM-3-high patients have a significantly reduced survival compared to sTIM-3-low patients, while they have similar survival probabilities under N + I. sTIM-3 is independent from other clinical and biological factors. Myeloid immune cells appear as the prominent source of sTIM-3, which may indicate their dysfunctional role in the antitumor immune response.</p><p><strong>Conclusions: </strong>sTIM-3 appears to be a promising biomarker for optimizing treatment strategies in ccRCC as well as a potential therapeutic target, linked with to the immune myeloid compartment. Future investigations are warranted in patients treated with anti-PD-1 + antiangiogenic therapies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"54"},"PeriodicalIF":11.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11827183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426584","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":"Protein phosphatase 1 regulatory subunit 15 A (PPP1R15A) promoted the progression of gastric cancer by activating cell autophagy under energy stress.","authors":"Yingnan Cui, Xueyuan Cao, Yangyu Zhang, Chenhao Fu, Dongming Li, Yuanlin Sun, Yuzheng Zhang, Tingshuang Xu, Tetsuya Tsukamoto, Donghui Cao, Jing Jiang","doi":"10.1186/s13046-025-03320-y","DOIUrl":"10.1186/s13046-025-03320-y","url":null,"abstract":"<p><strong>Background: </strong>Glucose metabolism plays a critical role in tumor progression. When glucose intake is insufficient and the tumor's growth rate exceeds its energy supply, tumor cells typically adapt and overcome the energy stress through compensatory mechanisms to maintain the survival of tumor cells, which may also be related to tumor recurrence or metastasis.</p><p><strong>Methods: </strong>Different concentrations of glucose were selected as the basis for the energy stress model of gastric cancer. Then CCK-8 and flow cytometry were used to detect its effects on cell proliferation, apoptosis, and cell cycle. Differentially expressed genes (DEGs) were screened by RNA sequencing and the regulated pathways were identified by gene set enrichment analysis. The regulatory relationship between the gene PPP1R15A and its transcription factor JUN was proved by ChIP-qPCR and dual-luciferase reporter assay. The gain and loss of function assays were conducted to examine the effects of PPP1R15A under energy stress in vivo and in vitro. Potential regulatory mechanisms of PPP1R15A were further analyzed through a combination of online databases, RNA sequencing, and metabolite sequencing. The regulation of PPP1R15A on cell autophagy under energy stress was detected by western blot, transmission electron microscope, mRFP-GFP-LC3 adenovirus and laser scanning confocal microscopy.</p><p><strong>Results: </strong>PPP1R15A and the transcription factor JUN were significantly upregulated by glucose deprivation (0 mM vs. 25 mM), JUN combined with the promoter of PPP1R15A and activated its expression. Both PPP1R15A and JUN were highly expressed in gastric cancer tissues and were independent risk factors for prognosis in the gastric cancer cohort. Overexpression of PPP1R15A promoted cell proliferation, inhibited apoptosis, and was involved in cell cycle arrest. Further RNA and metabolite sequencing suggested that PPP1R15A was associated with cell autophagy. In vitro experiments confirmed that both glucose deprivation and overexpression of PPP1R15A promoted the biosynthesis of autolysosome and autophagosome, and activated the cleavage of LC3 complex in gastric cancer cells. Moreover, PPP1R15A knockdown inhibited cell autophagy induced by glucose deprivation.</p><p><strong>Conclusions: </strong>PPP1R15A sustained the survival of gastric cancer cells by regulating autophagy under energy stress to resist or adapt to harsh environments.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"52"},"PeriodicalIF":11.4,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416094","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":"A scoping review of factors influencing the implementation of liquid biopsy for cancer care.","authors":"Samran Sheriff, Maree Saba, Romika Patel, Georgia Fisher, Tanja Schroeder, Gaston Arnolda, Dan Luo, Lydia Warburton, Elin Gray, Georgina Long, Jeffrey Braithwaite, Helen Rizos, Louise Ann Ellis","doi":"10.1186/s13046-025-03322-w","DOIUrl":"10.1186/s13046-025-03322-w","url":null,"abstract":"<p><strong>Background: </strong>Liquid biopsy (LB) offers a promising, minimally invasive alternative to traditional tissue biopsies in cancer care, enabling real-time monitoring and personalized treatment. Despite its potential, the routine implementation of LB in clinical practice faces significant challenges. This scoping review examines the barriers and facilitators influencing the implementation of liquid biopsies into standard cancer care.</p><p><strong>Methods: </strong>Four academic databases (PubMed, Scopus, Embase, and Web of Science) were systematically searched without language restrictions. We included peer-reviewed articles that were published between January 2019 and March 2024 that focused on the implementation of LB in cancer care or described barriers and facilitators to its implementation. Data relevant to the review objective, including key article characteristics; barriers and facilitators of implementation; and recommendations for advancement or optimisation; were extracted and analysed using thematic and visual network analyses.</p><p><strong>Results: </strong>The majority of the included articles were narrative review articles (84%), with most from China (24.2%) and the United States (20%). Thematic analysis identified four main categories and their associated barriers and facilitators to the implementation of LB in cancer care: (1) Laboratory and personnel requirements; (2) Disease specificity; (3) Biomarker-based liquid biopsy; and (4) Policy and regulation. The majority of barriers identified were concentrated in the pre-analytical phase, highlighting the lack of standardization in LB technologies and outcomes.</p><p><strong>Conclusions: </strong>Through a thematic analysis of the barriers and facilitators to LB implementation, we present an integrated tool designed to encourage the standardization of testing methods for clinical practice guidelines in the field.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"50"},"PeriodicalIF":11.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400544","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":"An IgE antibody targeting HER2 identified by clonal selection restricts breast cancer growth via immune-stimulating activities.","authors":"Lais C G F Palhares, Melanie Grandits, Katie Stoker, Jitesh Chauhan, Heng Sheng Sow, Gilbert O Fruhwirth, Sophia Tsoka, James Birtley, Leanne Partington, Tim Wilson, Elizabeth Hardaker, Sophia N Karagiannis, Heather J Bax, Kevin FitzGerald","doi":"10.1186/s13046-025-03319-5","DOIUrl":"10.1186/s13046-025-03319-5","url":null,"abstract":"<p><strong>Background: </strong>Tumor-targeting IgE antibodies have elicited potent tumor-restricting effects by recruiting immune effector mechanisms. However, a dedicated platform for the generation, selection and evaluation of novel IgEs based on target antigen recognition and functional profiles has not been reported.</p><p><strong>Methods: </strong>By establishing an IgE class antibody therapeutic design platform to allow selection of lead candidates, we generated a panel of IgEs recognising the human epidermal growth factor receptor 2 (HER2), overexpressed in 15-20% of breast cancers. From 1840 phage display-generated variable region sequences panned against HER2, we engineered 30 full length IgE antibodies. We selected three clones based on biophysical properties, reactivity to HER2 + cancer cells, epitope reactivity and Fc-mediated anti-tumor profiles in vitro. Clones with cross-reactivity to rat HER2 were selected to allow functional evaluations in a fully immunocompetent syngeneic HER2 + rat breast cancer model.</p><p><strong>Results: </strong>IgE antibodies induced degranulation and antibody-dependent cellular cytotoxicity against human and rat HER2-expressing tumor cells in vitro. IgE antibody 26 demonstrated anti-tumor activity in a syngeneic HER2 + rat model, and a human HER2 + breast cancer xenograft model in mice reconstituted with human immune cells. Treatment was associated with enhanced immune cell infiltration and pro-inflammatory immune signatures, and downregulated cancer progression signaling pathways, in the tumor microenvironment.</p><p><strong>Conclusions: </strong>This study pioneers the design and generation of anti-HER2 IgE lead antibody candidates with immune-stimulating and tumor-restricting effects. The present work may pave the way for antibody engineering therapeutic opportunities for challenging-to-treat HER2-expressing cancers.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"49"},"PeriodicalIF":11.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11818027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400550","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":"A combination of PD-1 and TIGIT immune checkpoint inhibitors elicits a strong anti-tumour response in mesothelioma.","authors":"Huaikai Shi, Ta-Kun Yu, Ben Johnson, Sakthi Priya Selvamani, Ling Zhuang, Kenneth Lee, Sonja Klebe, Samuel Smith, Kirby Wong, Kate Chen, Georgina Clark, Emma M Rath, Holly Pearson, David Gallego Ortega, Anthony Linton, Steven Kao, Pablo Silveira, Yuen Yee Cheng","doi":"10.1186/s13046-025-03314-w","DOIUrl":"10.1186/s13046-025-03314-w","url":null,"abstract":"<p><strong>Background: </strong>Finding effective and curative treatment for mesothelioma remains challenging. While the introduction of immunotherapy combinations using ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) have offered hope for some patients, a large proportion of mesothelioma cases, particularly the epithelial subtype, have minimal benefit from this.</p><p><strong>Methods: </strong>Our study was inspired by the results of the AdvanTG-105 phase I clinical trial, which showed partial response with anti-TIGIT/PD-1 treatment in two epithelioid mesothelioma patients. Here, we conducted a comprehensive in vivo experiment involving eight animal treatment groups administered with either PBS (control group), cisplatin/pemetrexed, anti-PD-1, anti-PD-1 + anti-CTLA-4, anti-TIGIT, anti-PD-1 + anti-TIGIT, anti-PD-1 + anti-CTLA-4 + anti-TIGIT, and cisplatin/pemetrexed + anti-PD-1 + anti-TIGIT.</p><p><strong>Results: </strong>Our results indicate that animals receiving anti-PD-1 + TIGIT exhibited a superior anti-tumour response, with 90% of the treatment group exhibiting an objective response, compared to 60%, 20% and 40% for the standard-of-care anti-PD-1 + CTLA-4, single-agent anti-PD-1 and cisplatin/pemetrexed treatment groups, respectively. Animals receiving anti-PD-1 + TIGIT displayed a significantly reduced average tumour size, with improved weight and survival rates, and fewer adverse effects than those receiving anti-PD-1 + CTLA-4 treatment. Anti-PD-1 + TIGIT-treated animals achieved complete tumour regression, with heightened effector CD8 + T cell and NK cell activity, remaining tumour-free for over 300 days without immune-related adverse events. After initial tumour elimination, anti-PD-1 + TIGIT-treated animals showed no tumour regrowth in the rechallenge experiment.</p><p><strong>Conclusion: </strong>These findings provide rationale for the development of an anti-PD-1 + TIGIT combination immunotherapy trial for mesothelioma patients.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"51"},"PeriodicalIF":11.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11816573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411380","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":"ELK3-CYFIP2 axis-mediated actin remodeling modulates metastasis and natural killer cell responses in triple-negative breast cancer.","authors":"Seung Hee Choi, Hye Jung Jang, Joo Dong Park, Ki Seo Ryu, Eunchong Maeng, Seohyun Cho, Hail Park, Hae-Yun Jung, Kyung-Soon Park","doi":"10.1186/s13046-025-03309-7","DOIUrl":"10.1186/s13046-025-03309-7","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) is an aggressive, highly metastatic disease with a poor prognosis. E26 transformation-specific transcription factor (ELK3) is highly expressed in TNBCs, and functions as a regulator of epithelial-mesenchymal transition and immune responses. Because metastatic migration and immune evasion by TNBC cells are critical factors for successful metastasis, unravelling the underlying mechanisms and developing effective immunotherapeutic strategies is urgent. Here, TNBC cell lines MDA-MB-231 and Hs578T were examined to determine the relationship between ELK3 expression and filopodia protrusion on the cell membrane, as well as actin accumulation at contact sites with natural killer (NK) cells. RNA-sequencing analysis and molecular experiments were conducted to identify and validate downstream target genes of ELK3 associated with migration and attachment of TNBC cells. The immune response of TNBC to NK cells was evaluated through imaging and flow cytometry analyses. Clinical significance was assessed through Kaplan-Meier analysis of survival outcomes of TNBC patients. Gene expression profiling and molecular analysis revealed that oncogenic ELK3 directly suppresses expression of cytoplasmic FMR1 interacting protein2 (CYFIP2), a repressor of actin accumulation. Further molecular and pharmacological analyses confirmed that the ELK3-CYFIP2 axis serves a dual role in TNBC cell lines by (1) controlling filopodia-mediated migration and adhesion by regulating actin accumulation, and (2) regulating sensitivity to NK cells by modulating actin accumulation at contact sites. Kaplan-Meier analysis suggested that ELK3-CYFIP2 axis is associated with survival of TNBC patients, and that ELK3 suppresses transcription of CYFIP2. Thus, the ELK3-CYFIP2 axis plays a pivotal role in regulating actin, emphasizing its significance in controlling both cancer cell migration and NK cell responses in TNBC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"48"},"PeriodicalIF":11.4,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11808954/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391952","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":"Tumor secretome shapes the immune landscape during cancer progression.","authors":"Jianqiang Yang, Sijia Tang, Nabil F Saba, Chloe Shay, Yong Teng","doi":"10.1186/s13046-025-03302-0","DOIUrl":"10.1186/s13046-025-03302-0","url":null,"abstract":"<p><p>The focus of cancer immunotherapy has traditionally been on immune cells and tumor cells themselves, often overlooking the tumor secretome. This review provides a comprehensive overview of the intricate relationship between tumor cells and the immune response in cancer progression. It highlights the pivotal role of the tumor secretome - a diverse set of molecules secreted by tumor cells - in significantly influencing immune modulation, promoting immunosuppression, and facilitating tumor survival. In addition to elucidating these complex interactions, this review discusses current clinical trials targeting the tumor secretome and highlights their potential to advance personalized medicine strategies. These trials aim to overcome the challenges of the tumor microenvironment by designing therapies tailored to the secretome profiles of individual cancer patients. In addition, advances in proteomic techniques are highlighted as essential tools for unraveling the complexity of the tumor secretome, paving the way for improved cancer treatment outcomes.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"47"},"PeriodicalIF":11.4,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391955","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":"Correction: Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma.","authors":"Jin Wang, Xiaoyang Liu, Yongzhi Hong, Songtao Wang, Pin Chen, Aihua Gu, Xiaoyuan Guo, Peng Zhao","doi":"10.1186/s13046-025-03304-y","DOIUrl":"10.1186/s13046-025-03304-y","url":null,"abstract":"","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"46"},"PeriodicalIF":11.4,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809083/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143384025","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":"Dysbiosis and extraintestinal cancers.","authors":"Ruishan He, Pingqian Qi, Linzhen Shu, Yidan Ding, Peng Zeng, Guosheng Wen, Ying Xiong, Huan Deng","doi":"10.1186/s13046-025-03313-x","DOIUrl":"10.1186/s13046-025-03313-x","url":null,"abstract":"<p><p>The gut microbiota plays a crucial role in safeguarding host health and driving the progression of intestinal diseases. Despite recent advances in the remarkable correlation between dysbiosis and extraintestinal cancers, the underlying mechanisms are yet to be fully elucidated. Pathogenic microbiota, along with their metabolites, can undermine the integrity of the gut barrier through inflammatory or metabolic pathways, leading to increased permeability and the translocation of pathogens. The dissemination of pathogens through the circulation may contribute to the establishment of an immune-suppressive environment that promotes carcinogenesis in extraintestinal organs either directly or indirectly. The oncogenic cascade always engages in the disruption of hormonal regulation and inflammatory responses, the induction of genomic instability and mutations, and the dysregulation of adult stem cell proliferation. This review aims to comprehensively summarize the existing evidence that points to the potential role of dysbiosis in the malignant transformation of extraintestinal organs such as the liver, breast, lung, and pancreas. Additionally, we delve into the limitations inherent in current methodologies, particularly the challenges associated with differentiating low loads gut-derived microbiome within tumors from potential sample contamination or symbiotic microorganisms. Although still controversial, an understanding of the contribution of translocated intestinal microbiota and their metabolites to the pathological continuum from chronic inflammation to tumors could offer a novel foundation for the development of targeted therapeutics.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"44"},"PeriodicalIF":11.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143366696","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":"VSIG4⁺ tumor-associated macrophages mediate neutrophil infiltration and impair antigen-specific immunity in aggressive cancers through epigenetic regulation of SPP1.","authors":"Zongfu Pan, Jinming Chen, Tong Xu, Anqi Cai, Bing Han, Ying Li, Ziwen Fang, Dingyi Yu, Shanshan Wang, Junyu Zhou, Yingying Gong, Yulu Che, Xiaozhou Zou, Lei Cheng, Zhuo Tan, Minghua Ge, Ping Huang","doi":"10.1186/s13046-025-03303-z","DOIUrl":"10.1186/s13046-025-03303-z","url":null,"abstract":"<p><p>V-set and immunoglobulin domain-containing 4 (VSIG4) positive tumor-associated macrophage (VSIG4⁺ TAM) is an immunosuppressive subpopulation newly identified in aggressive cancers. However, the mechanism how VSIG4⁺ TAMs mediate immune evasion in aggressive cancers have not been fully elucidated. In our study, we found targeting VSIG4⁺ TAMs by VSIG4 deficiency or blockade remarkably limited tumor growth and metastasis, especially those derived from anaplastic thyroid cancer (ATC) and pancreatic cancer, two extremely aggressive types. Moreover, the combination of VSIG4 blockade with a BRAF inhibitor synergistically enhanced anti-tumor activity in ATC-tumor bearing mice. VSIG4 deficiency recovered the antigen presentation (B2m, H2-k1, H2-d1) of TAMs and activated antigen-specific CD8⁺ T cells by promoting their in vivo proliferation and intratumoral infiltration. Notably, loss of VSIG4 in TAMs significantly reduced the production of lactate and histone H3 lysine 18 lactylation, resulting the decreased transcription of SPP1 mediated by STAT3, which collectively disrupted the cell-cell interactions between TAMs and neutrophils. Further combination of VSIG4 with SPP1 blockade synergistically boosted anti-tumor activity. Overall, our studies demonstrate the epigenetic regulation function of VSIG4 confers on TAMs an alternative pattern, beyond the checkpoint role of VSIG4, to shape the immunosuppressive tumor microenvironment and impair antigen-specific immunity against aggressive cancers.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"45"},"PeriodicalIF":11.4,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11803937/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371437","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}