Cancer immunology research最新文献

{"title":"TIGIT affects CAR NK cell effector function in the solid tumor microenvironment by modulating immune synapse strength.","authors":"Ishwar Navin, Matthew Dysthe, Prashant S Menon, Corrine Baumgartner, Tim Sauer, Navin Varadarajan, Robin Parihar","doi":"10.1158/2326-6066.CIR-24-0919","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0919","url":null,"abstract":"<p><p>Therapies using natural killer (NK) cells that express chimeric antigen receptors (CAR-NKs) have been successfully employed against hematological malignancies. However, solid tumors resist CAR NKs partly by enriching tumor microenvironments with ligands for NK cell inhibitory receptors. Although the NK inhibitory receptor TIGIT has been implicated in impaired anti tumor activity of endogenous NK cells, the consequences of TIGIT expression on engineered CAR NKs has not been explored. To address this gap, we compared TIGIT-expressing and TIGIT deleted human CAR-NKs targeting the GD2 solid tumor antigen in tumor immune microenvironment (TiME) co-cultures and in vivo TiME xenografts designed to mimic the immunosuppressive environment of solid tumors. TIGIT deleted GD2.CAR-NKs exhibited antitumor activity, expanded, and persisted within TIGIT ligand enriched solid tumor environments while TIGIT expressing CAR-NKs did not. Mechanistic experiments revealed that the improved tumor control resulting from TIGIT loss on CAR-NKs was not dependent on DNAM-1 activation or enhanced cytotoxic potential, but rather on downregulation of cell adhesion molecules, weakened cell avidity, and reduced synapse contact duration that, in concert, improved serial killing and allowed more efficient tumor destruction. Our study highlights a novel non canonical role for TIGIT in modulating CAR-NK activity that may guide strategies to overcome inhibitory NK receptors like TIGIT and improve efficacy of CAR NKs against solid tumors.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144741284","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":"SPP1+ Tumor-associated Macrophages Drive Immunotherapy Resistance via CD8+ T-Cell Dysfunction in Clear Cell Renal Cell Carcinoma.","authors":"Wenbin Jiang, Li Liu, Ziyang Xu, Youqi Qiu, Boyu Zhang, Jiangting Cheng, Jiyan Luo, Yang Qu, Jianming Guo, Jiejie Xu","doi":"10.1158/2326-6066.CIR-24-1146","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1146","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are key regulators of tumor immunity. With advances in single-cell analyses, SPP1+ TAMs have been observed across multiple tumor sites. However, their clinical relevance and phenotypic characteristics in clear cell renal cell carcinoma (ccRCC) have not been comprehensively delineated. Using patient-level data from two in-house cohorts (n=355) we explored the relationship between SPP1+ TAM infiltration and therapeutic response as well as prognosis in ccRCC. Four publicly available datasets consisting of 1,741 ccRCC patients were included for external validation. Cytometry by time-of-flight (CyTOF) and flow cytometry were utilized to phenotype SPP1+ TAMs and establish their impact on CD8+ T cells. Further, we established an ex vivo culture system to test the potential therapeutic value of targeting SPP1 alone and in conjunction with PD-1 inhibitors in ccRCC. We found that patients with high SPP1+ TAM infiltration exhibited worse response to immunotherapy and dismal prognosis in ccRCC. SPP1+ TAMs exhibited an immunosuppressive and pro-tumor phenotype, and were related to impaired effector function and terminal differentiation of CD8+ T cells. Blockade of SPP1 mitigated the pro-tumor tumor microenvironment and reinvigorated CD8+ T-cell function. Combining PD-1 blockade with SPP1 blockade boosted the expansion of CD8+ T cells and enhanced antitumor efficacy. Together, these data indicate that elevated infiltration of SPP1+ TAMs is related to worse response to immunotherapy and dysfunction of CD8+ T cells in ccRCC. We conclude that SPP1 may serve as a potential therapeutic target in ccRCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144663871","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":"EML4-ALK rearrangement creates a distinctive myeloid cell-dominant immunosuppressive microenvironment in lung cancer.","authors":"Kosuke Arai, Yukari Nishito, Hideaki Mizuno, Noriko Motoi, Nobuyoshi Hiraoka, Masanori Fuse, Yasuhito Arai, Tatsuhiro Shibata, Yukiko Sonobe, Yoko Kayukawa, Toru Maruyama, Hironori Fukuda, Yukihiro Mizoguchi, Yukiko Aikawa, Yukihiro Yoshida, Shun-Ichi Watanabe, Hiromi Sakamoto, Makiko Yamashita, Shigehisa Kitano, Yuki Nagata, Risa Mitsumori, Kouichi Ozaki, Shumpei Niida, Yae Kanai, Akiyoshi Hirayama, Tomoyoshi Soga, Teruhiko Yoshida, Kazuki Yasuda, Atsushi Ochiai, Hiroyuki Tsunoda, Kazunori Aoki","doi":"10.1158/2326-6066.CIR-24-0532","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-0532","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors (TKIs) are initially efficacious against anaplastic lymphoma kinase (ALK) fusion gene-positive lung adenocarcinoma (ALK+ LUAD), but acquired resistance inevitably occurs. Therefore, alternative treatment strategies are needed for TKI-resistant cases. Although the use of immune checkpoint inhibitors (ICIs) has improved the prognosis of patients with lung cancer, patients with ALK+ LUAD exhibit little or no response to immunotherapy and the underlying resistance mechanisms remain unknown. Here, we explored the immunological status of the tumor microenvironment (TME) in ALK+ LUAD tissues. Tumor-infiltrating leukocyte analysis revealed reduced numbers of effector T cells and increased myeloid-derived suppressor cells (MDSCs) relative to ALK- LUAD cases, indicating that ALK+ LUAD has a myeloid cell-dominant immunosuppressive TME. Single-cell RNA-sequencing analysis identified a subset of macrophages that expressed most T cell-attractant chemokines (CXCL9, CXCL10, and CXCL11), and the macrophages were inactivated in ALK+ LUAD. In contrast, ALK+ LUAD expressed high levels of MDSC-attractant chemokines (CXCL1 and CXCL8). In addition, ALK+ LUAD showed higher levels of IL-6, an MDSC-inducing cytokine, than ALK- LUAD. An IL-6R inhibitor transformed the TME in a murine ALK+ LUAD model, shifting it from an immunosuppressive to a T cell-dominant status. Although ICI monotherapy lacked antitumor effects, a combination of ICI and the IL-6R inhibitor had significant antitumor effects in mice. Our findings illustrate the molecular basis of fusion gene-mediated immunosuppressive TMEs, providing a rationale for a novel combination immunotherapy for ALK+ LUAD.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590507","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":"Vγ9Vδ2 T Cells Express an Antitumor Profile Associated with Anti-PD-(L)1 Responses and Activation Defects Restored by Anti-BTN3A in Triple-Negative Breast Cancer.","authors":"Stéphane Fattori, Laurent Gorvel, Marie-Sarah Rouvière, Samuel Granjeaud, Amira Ben Amara, Manon Richaud, Nicolas Boucherit, Carole Tarpin, Jihane Pakradouni, Julien Hédou, Grégoire Bellan, Brice Gaudilliere, Emmanuelle Charafe-Jauffret, Gilles Houvenaeghel, Eric Lambaudie, François Bertucci, Jean-Jacques Fournié, Anthony Gonçalves, Philippe Rochigneux, Anne-Sophie Chrétien, Daniel Olive","doi":"10.1158/2326-6066.CIR-24-1285","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1285","url":null,"abstract":"<p><p>Vγ9Vδ2 (TCRVγ9+ TCRVδ2+) T cells are promising immunotherapeutic targets with effective antitumor properties in both in vitro and preclinical models of triple-negative breast cancer (TNBC). However, no information regarding their potential role in the context of human TNBC progression and response to immunotherapy has been reported. One key reason for this is the scarcity of Vγ9Vδ2 T cell infiltrates relative to their Vδ1 (TCRVδ1+) and αβCD8 (TCRαβ+ CD8αβ+) T cell counterparts. We provide a comprehensive single-cell profiling of Vγ9Vδ2 T cells from patients with TNBC, prior to and following PD-(L)1 blockade therapy. We report that baseline Vγ9Vδ2 T cell infiltrate expressing a unique cytotoxic type-I (Tc1) phenotype could be associated with improved survival in patients with TNBC. Vγ9Vδ2 T cells harboring characteristics of enhanced antitumor activity (KLRC1+) were further associated with improved response to PD-(L)1 blockade therapy in patients with TNBC. Vγ9Vδ2 T cells had low expression levels of T cell exhaustion (PD-1Low TOXLow) and TCR signaling hallmarks compared to Vδ1 and αβCD8 T cells, along with skewed differentiation profiles towards early effector memory phenotypes, both before and after anti-PD-1 therapy in TNBC tumors. Consistently, we observed a limited activity of anti-PD-1 on tumor-infiltrating Vγ9Vδ2 T cells. In vitro, the use of anti-butyrophilin-3A (BTN3A) antibodies in addition to the anti-PD-1 reinvigorated the Tc1 functions of peripheral Vγ9Vδ2 T cells from patients with breast cancer. Together, these data provide a rationale for Vγ9Vδ2 T cell-based combination therapy in patients with TNBC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583085","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":"A Dendritic Cell-Like Transition of T Cells Is Associated with Spontaneous Remission of Adult T-Cell Leukemia-Lymphoma.","authors":"Miho Watanabe, Jun-Ichirou Yasunaga, Osama Hussein, Azusa Tanaka, Takafumi Shichijo, Mikiko Izaki, Yuki Okamoto, Yoshihiro Komohara, Masao Matsuoka","doi":"10.1158/2326-6066.CIR-24-0306","DOIUrl":"10.1158/2326-6066.CIR-24-0306","url":null,"abstract":"<p><p>Spontaneous remission in patients with various cancers has been reported. Some patients with adult T-cell leukemia-lymphoma (ATL) have experienced spontaneous remission, although the mechanisms for this remain unknown. In this study, we analyzed ATL cells and human T-cell leukemia virus type 1 (HTLV-1)- infected cells using cytometry by time-of-flight mass spectrometry. We observed a small number (less than 5% on average) of ATL cells and HTLV-1-infected cells that expressed CD14 and other dendritic cell (DC)-associated molecules such as CD1c, CD11b, CD11c, and CD141. Single-cell analysis revealed that these T cells expressing DC markers also contained rearranged T-cell receptor genes, indicating that these cells are indeed derived from T cells. In a patient with ATL who entered remission after contracting coronavirus disease 2019, the number of DC-like T cells increased, and an enzyme-linked immunosorbent spot assay detected CTLs against the Tax protein in accordance with a regression of ATL. These findings suggest that DC-like ATL cells acquire antigen-presenting capability and induce spontaneous remission through enhanced immunity to the virus. Specifically, in an ATL cell line, enforced expression of IRF8 and PU.1, in addition to endogenous BATF3 expression, increased CD86 expression and enabled the cells to present Tax peptide antigens to T cells. Collectively, these data indicate that ATL cells acquire antigen-presenting activity when IRF8, PU.1, and BATF3 are expressed, suggesting that the transition of a subset of T cells to DC-like T cells can induce immune responses to viral antigens, resulting in spontaneous remission. Thus, the transition of T cells to DC-like T cells is a unique mechanism for spontaneous remission in ATL.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1098-1110"},"PeriodicalIF":8.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143977747","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":"Artificial Intelligence Can Predict Personalized Immunotherapy Outcomes in Cancer.","authors":"Ling Huang, Xuewei Wu, Jingjing You, Zhe Jin, Wenle He, Jie Sun, Hui Shen, Xin Liu, Xin Yue, Wenli Cai, Shuixing Zhang, Bin Zhang","doi":"10.1158/2326-6066.CIR-24-1270","DOIUrl":"10.1158/2326-6066.CIR-24-1270","url":null,"abstract":"<p><p>The rapid advancement of artificial intelligence (AI) technologies has opened new avenues for advancing personalized immunotherapy in cancer treatment. This review highlights current research progress in applying AI to optimize the use of immunotherapy for patients with cancer. Recent studies demonstrate that AI models can accurately diagnose cancers and discover biomarkers by integrating multi-omics and imaging data, establish predictive models to estimate treatment responses and adverse reactions, formulate personalized treatment plans integrating multiple modalities by considering various factors, and achieve precise patient stratification and clinical trial matching, thereby addressing specific obstacles throughout processes from diagnosis to treatment in personalized immunotherapy. Furthermore, this review also discusses the challenges and limitations faced by AI in clinical applications, such as difficulties in data acquisition, low quality of data, poor interpretability of models, and insufficient generalization ability. Finally, we outline future research directions, including optimizing data management, developing explainable AI, and improving the generalization ability of models. These efforts aim to optimize the role of AI in personalized immunotherapy and promote the development of precision medicine. To ensure the clinical applicability of these AI models, large-scale studies, multi-omics integration, and prospective clinical trials are necessary.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"964-977"},"PeriodicalIF":8.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274255","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":"Identification of the Distinct Immune Microenvironment Features Associated with Progression Following High-Dose Melphalan and Autologous Stem Cell Transplant in Multiple Myeloma.","authors":"Parvathi Sudha, Travis S Johnson, Habib Hamidi, Ke Yang, Enze Liu, Brent Smith, Vivek Chopra, Michael Nixon, Faiza Zafar, Sherif S Farag, Gareth J Morgan, Ola Landgren, Kelvin Lee, Attaya Suvannasankha, Magdalena Czader, Rafat Abonour, Mohammad Abu Zaid, Brian A Walker","doi":"10.1158/2326-6066.CIR-25-0019","DOIUrl":"10.1158/2326-6066.CIR-25-0019","url":null,"abstract":"<p><p>A key treatment for patients with multiple myeloma is high-dose melphalan followed by autologous stem cell transplant (ASCT). It can provide a deep response with long-term remission. However, some patients progress quickly, and it is not clear why. In this study, we performed single-cell RNA and T-cell receptor sequencing of the immune microenvironment of 40 patients before and after ASCT to determine if differences in the immune composition could define those who would progress. Clear differences in cell populations were identified in progressors, including increased T-cell infiltration, decreased T-cell receptor diversity, and decreased frequency of monocytes and CD56bright NK cells. We identified cell interactions that predicted progression, including increased frequency of CD8+ exhausted T cells and stromal cells and decreased frequency of CD56bright NK cells and plasmacytoid dendritic cells. We propose and validate a model of progression that can also be determined by flow cytometry. Together, these data highlight the importance of the immune microenvironment in understanding responses to ASCT.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1070-1079"},"PeriodicalIF":8.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12214876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143974034","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":"Regulatory T cells poise the myeloid landscape after chemotherapy in lung tumors.","authors":"Eléonore Weber-Delacroix, Marylou Panouillot, Marie Laviron, François Lanthiez, Tristan Philippe, Sandrine Barthélémy, Solène Fastenackels, Armanda Casrouge, Benoit L Salomon, Ingrid Sassoon, Jeremy Baudhuin, Ilaria Onorati, Marianne Kambouchner, Nahla Cucherousset, Christophe Combadière, Boris Duchemann, Marie-Caroline Dieu-Nosjean, Alexandre Boissonnas","doi":"10.1158/2326-6066.CIR-25-0103","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0103","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are major immune components of the tumor microenvironment, promoting tumor growth and limiting the efficacy of chemotherapy in almost all cancer indications. While Tregs are well known for their immune suppressive activity toward the adaptive immune system, less is known about their regulatory activity toward the innate compartment. We showed in human and mouse lung cancer, that chemotherapy transiently reduced Treg number and switched the mononuclear phagocyte (MP) landscape toward a pro-inflammatory signature but also an increased TGFβ-expressing TAM accumulation over time. Preventing Treg recovery further increased the recruitment of monocytes and limited TGFβ expression upon TAM differentiation, demonstrating that Tregs dampen the pro-inflammatory status of the MP compartment induced by chemotherapy and promote tumor relapse. Anti-TNFR2 antibody treatment during the Treg recovery phase affected the direct interaction between Tregs and MPs, increased the pro-inflammatory signature of the MPs and improved survival in the mouse model. Targeting the crosstalk between tumor-associated Tregs and the MP compartment limits the reconstitution of an anti-inflammatory environment following chemotherapy and improves therapeutic outcome.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144552395","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":"Somatic Mutations in HLA Class Genes and Antigen-Presenting Molecules in Malignant Glioma.","authors":"Sara C Schulte, Wolfgang Peter, Georg Rosenberger, Moritz Schäfer, Cecile L Maire, Alessandra Rünger, Alice Ryba, Kristoffer Riecken, Krystian D Fita, Jakob Matschke, Nuray Akyüz, Judith Dierlamm, Gunnar W Klau, Franz L Ricklefs, Jens Gempt, Manfred Westphal, Katrin Lamszus, Alexander Dilthey, Malte Mohme","doi":"10.1158/2326-6066.CIR-24-0419","DOIUrl":"10.1158/2326-6066.CIR-24-0419","url":null,"abstract":"<p><p>Immune evasion is a hallmark of gliomas, yet the genetic mechanisms by which tumors escape immune surveillance remain incompletely understood. In this study, we systematically examined the presence of somatic mutations in HLA genes and genes encoding proteins involved in antigen presentation across isocitrate dehydrogenase wild-type and mutant gliomas using targeted next-generation sequencing. To address the challenges associated with detecting somatic mutations in these highly polymorphic and complex regions of the genome, we applied a combination of short-read and long-read sequencing techniques, extended the genetic region of interest (exons and introns), and applied a tailored bioinformatics analysis pipeline, which enabled an accurate evaluation of comprehensive sequencing data. Our analysis identified mutations in HLA class II and nonclassic HLA genes as well as genes associated with antigen presentation, such as TAP1/2 and B2M. Three-dimensional modeling of individual mutations simulated the potential impact of somatic mutations in TAP1 and B2M on the encoded protein configuration. The presence of somatic mutations supports the role of antigen-presenting genes in the pathophysiology and potential immune escape of gliomas. Our data demonstrated an increased frequency of such mutations in recurrent glioblastoma, potentially resulting from a positive selection or mutagenic enrichment of tumor cells during tumor progression. Taken together, this research generates new insights and hypotheses for the functional analysis and optimization of immunotherapy strategies for gliomas, which may guide personalized treatment paradigms.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1111-1123"},"PeriodicalIF":8.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954635","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":"METTL3 Inhibition Restores PD-L1 Expression and CD8+ T-cell Cytotoxic Function in Immunotherapy-Treated Gastric Cancer.","authors":"Ming Fang, Yaling Li, Peng Wang, Yanan Wang, Xiaoqian Wang, Xiaoxia Wa, Yu Zhang, Zhenyu He, Jiawei Li, Ling Li, Yun Su, Huinian Zhou, Jianzheng He, Yongqi Liu","doi":"10.1158/2326-6066.CIR-24-1179","DOIUrl":"10.1158/2326-6066.CIR-24-1179","url":null,"abstract":"<p><p>The efficacy of immunotherapy targeting PD-1/PD-L1 in gastric cancer depends on PD-L1 expression levels and the infiltration of immune cells within the tumor microenvironment (TME). Although methyltransferase-like 3 (METTL3) plays a role in the development and progression of gastric cancer, its mechanism of regulating the TME in gastric cancer remains unclear. In this study, we demonstrated that the expression of PD-L1 is regulated by METTL3. We found that METTL3 mediated N6-methyladenosine (m6A) modification of PDL1 mRNA in the 3' untranslated region and induced mRNA degradation through an m6A/YTHDF2-dependent pathway in human gastric cancer cells. METTL3 knockdown or inhibition in gastric cancer cells significantly enhanced Jurkat cell migration and cytotoxic activity. In clinical gastric cancer tissue, a negative correlation was observed between the expression levels of PD-L1 and those of METTL3 or YTHDF2. In vivo, combination treatment with the METTL3 inhibitor STM2457 and PD-1 mAb resulted in a significant reduction in tumor growth, enhanced PD-L1 expression, and increased infiltration of CD8+ T cells. Finally, lower METTL3 expression in tumors correlated with improved sensitivity to anti-PD-1 immunotherapy in patients. Our findings revealed that METTL3-mediated m6A modification of PDL1 mRNA levels represents an epigenetic mechanism regulating antitumor immunity in gastric cancer, and inhibiting METTL3 during PD-1 mAb treatment reshaped the TME, thereby establishing a promising treatment approach for enhancing immunotherapy efficacy in patients with gastric cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1037-1052"},"PeriodicalIF":8.1,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143972842","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}