Cancer immunology research最新文献

{"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":"10.1158/2326-6066.CIR-24-0532","url":null,"abstract":"<p><p>Tyrosine kinase inhibitors are initially efficacious against anaplastic lymphoma kinase (ALK) fusion gene-positive lung adenocarcinoma, but acquired resistance inevitably occurs. Therefore, alternative treatment strategies are needed for tyrosine kinase inhibitor-resistant cases. Although the use of immune checkpoint inhibitors (ICI) has improved the prognosis of patients with lung cancer, patients with ALK+ lung adenocarcinoma exhibit little or no response to immunotherapy and the underlying resistance mechanisms remain unknown. In this study, we explored the immunologic status of the tumor microenvironment (TME) in ALK+ lung adenocarcinoma tissues. Tumor-infiltrating leukocyte analysis revealed reduced numbers of effector T cells and increased myeloid-derived suppressor cells (MDSC) relative to ALK- lung adenocarcinoma cases, indicating that ALK+ lung adenocarcinoma 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+ lung adenocarcinoma. In contrast, ALK+ lung adenocarcinoma expressed high levels of MDSC-attractant chemokines (CXCL1 and CXCL8). In addition, ALK+ lung adenocarcinoma showed higher levels of IL6, an MDSC-inducing cytokine, than ALK- lung adenocarcinoma. An IL6R inhibitor transformed the TME in a murine ALK+ lung adenocarcinoma model, shifting it from an immunosuppressive to a T cell-dominant status. Although ICI monotherapy lacked antitumor effects, a combination of ICI and the IL6R 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+ lung adenocarcinoma. See related Spotlight by Vitale and Bria, p.1326.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1435-1452"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","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":"Unlocking the Immune Response in ALK-Rearranged Lung Adenocarcinoma.","authors":"Antonio Vitale, Emilio Bria","doi":"10.1158/2326-6066.CIR-25-0624","DOIUrl":"10.1158/2326-6066.CIR-25-0624","url":null,"abstract":"<p><p>Anaplastic lymphoma kinase-rearranged lung adenocarcinoma (ALK+ LUAD) is currently considered an immune-resistant disease, yet underlying biological mechanisms are largely unknown. In this issue, Arai and colleagues analyzed the tumor microenvironment (TME) in ALK+ LUADs, identifying a myeloid cell-dominant immunosuppressive TME, primarily driven by IL6 secretion. Dual anti-IL6R/anti-PD-L1 treatment resulted in robust antitumor effect in mouse models, restoring immune sensitivity and tumor control. These findings highlight a promising therapeutic approach to enhance the efficacy of PD-(L)1 inhibitors by reverting TME-mediated immune resistance, reshaping the role of immunotherapy in ALK+ LUADs. See related article by Arai et al., p. 1435.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1326-1327"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144798235","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 Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.","authors":"","doi":"10.1158/2326-6066.CIR-13-9-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-13-9-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"13 9","pages":"1325"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944040","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":"RORγt Inhibition Reduces Protumor Inflammation and Decreases Tumor Growth in Experimental Models of Lung Cancer.","authors":"Miki Yamada-Hara, Lauren Amaya, Zhihe Wang, Ji Won Byun, Naoki Takahashi, Sunandini Sharma, Han Chang, Arisachi Tanaka, Liping Zeng, Zahra Malakoutikhah, Sneha Ganguly, Minh-Chau Vu, Matt Levin, David Schwartz, Jack Heath, Scott Herdman, Maripat Corr, Eyal Raz, Samuel Bertin","doi":"10.1158/2326-6066.CIR-24-1128","DOIUrl":"10.1158/2326-6066.CIR-24-1128","url":null,"abstract":"<p><p>The retinoic acid receptor-related orphan receptor C (RORC) gene encodes two isoforms, RORγ and RORγt, which function as transcription factors in different cell types. RORγt is expressed in specific immune cells involved in inflammatory responses, whereas RORγ is found in parenchymal cells, in which it participates in metabolism and circadian rhythm regulation. Although the roles of RORγt in CD4+ Th17 lymphocytes and RORγ in certain cancer cell types are increasingly recognized, their relative contributions to lung cancer development remain unclear. In this study, we investigated the roles of RORC, RORγ, and RORγt in lung cancer using mouse models and human data from The Cancer Genome Atlas. We evaluated the effects of Rorc gene deletion and RORγ/γt pharmacologic inhibition in cancer and immune cells in vitro and in vivo. Pharmacologic blockade of RORγ/γt with digoxin significantly reduced lung cancer development in two mouse models: a KrasG12D-driven genetic model and a urethane-induced chemical model. Mechanistically, this effect was mediated by inhibition of RORγt in specific immune cells, such as type 3 innate lymphoid cells and Th17 cells, rather than by inhibiting RORγ in tumor cells. This reduced the production of proinflammatory cytokines, including IL17A, IL17F, and IL22, and decreased tumor cell proliferation. Additionally, The Cancer Genome Atlas analysis revealed that elevated RORC expression is associated with an altered tumor microenvironment and poorer prognosis in patients with lung adenocarcinoma. These findings highlight the therapeutic potential of targeting RORγt to reduce protumor inflammation and propose a strategy for lung cancer treatment.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1418-1434"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324574","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":"Close Spatial Interactions between Cancer Cells and Cancer-Associated Fibroblasts Suppress Antitumor Immunity.","authors":"Yuto Naoi, Yumi Inukai, Tomoka Izumikawa, Joji Nagasaki, Takamasa Ishino, Youki Ueda, Yin Min Thu, Miho Fujiwara, Takahiro Baba, Go Makimoto, Ken Suzawa, Kazuhiro Okada, Ken-Ichi Yamamoto, Masakiyo Sakaguchi, Shuta Tomida, Yoshinobu Maeda, Shinichi Toyooka, Mizuo Ando, Yosuke Togashi","doi":"10.1158/2326-6066.CIR-24-1144","DOIUrl":"10.1158/2326-6066.CIR-24-1144","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAF) play immunosuppressive roles in the tumor microenvironment. Specifically, they reportedly act as physical barriers preventing immune cell infiltration. However, the spatial relationships between CAFs and cancer cells in antitumor immunity remain unknown. In this study, we established three-dimensional (3D) constructs, in which the spatial relationships were controlled using a 3D bioprinter. Using these models, we found that the mixed distribution of fibroblasts (FB) and cancer cells suppressed the antitumor immunity more than the surrounding distribution of FBs as physical barriers. The 3D construct with mixed distribution promoted TGFβ and periostin (encoded by Postn gene) cross-talk, resulting in immunosuppression. Postn knockdown in FBs decreased the TGFβ production in the mixed 3D construct and activated antitumor immunity both in vitro and in vivo. Clinically, patients with head and neck cancer or lung cancer showing a mixed distribution of α-smooth muscle actin+ myofibroblast-like CAFs exhibited worse prognosis after PD-1 blockade therapies, and lower CD8+ T-cell infiltration than those that had CAFs surrounding cancer cells. Overall, our findings suggest that the close interactions of CAFs and cancer cells facilitate immunosuppression, rather than the physical barriers created by CAFs, highlighting their potential as biomarkers and therapeutic targets for cancer immunotherapies based on spatial relationships. Furthermore, this study highlights the beneficial applications of 3D bioprinters.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1471-1484"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539068","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":"Harnessing Notch Signaling to Enhance the Generation and Functionality of Human Conventional Type 1 Dendritic Cells for Cancer Immunotherapy Applications.","authors":"Sreekumar Balan, Liam O'Brien, Ante Peros, Xuedi Wang, Ingrid Leal Rojas, Christopher McClain, Kristen J Radford, Nina Bhardwaj","doi":"10.1158/2326-6066.CIR-25-0034","DOIUrl":"10.1158/2326-6066.CIR-25-0034","url":null,"abstract":"<p><p>A dendritic cell (DC)-based vaccine, Sipuleucel-T, remains the sole FDA-approved cancer vaccine. Despite their established safety and efficacy against cancers and infections in numerous trials, long-term clinical benefits have been modest. Most trials have employed DCs derived from blood monocytes, but emerging evidence underscores the unique role of conventional type 1 DCs (cDC1) in triggering potent antitumor immune responses and their intratumoral infiltration with favorable prognoses in many cancers. However, the scarcity of cDC1s in peripheral blood and the challenges in generating them in vitro have hindered a deeper understanding of their biology and their widespread application as cellular vaccines. In this study, we present a serum-free culture system capable of generating billions of human cDC1s from CD34+ progenitors derived from cord or peripheral blood. The system leverages the requirement of Notch signaling for cDC1 differentiation and generates DCs that closely resemble in vivo cDC1s, exhibiting functions including cellular antigen cross-presentation. This robust protocol enables the scalable production of cDC1s for both fundamental biological research and therapeutic applications.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1328-1341"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144539069","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":"GPC2-Targeted CAR T Cells Engineered with NFAT-Inducible Membrane-Tethered IL15/IL21 Exhibit Enhanced Activity against Neuroblastoma.","authors":"Reona Okada, Jeyshka M Reyes-González, Constanza Rodriguez, Taisuke Kondo, Jangsuk Oh, Ming Sun, Michael C Kelly, Ling Zhang, James Gulley, Jack F Shern, Mitchell Ho, Christian S Hinrichs, Naomi N Taylor, Xiyuan Zhang, Rosa Nguyen","doi":"10.1158/2326-6066.CIR-24-0975","DOIUrl":"10.1158/2326-6066.CIR-24-0975","url":null,"abstract":"<p><p>Neuroblastoma is a highly aggressive childhood solid tumor with poor outcomes. Chimeric antigen receptor (CAR) T cells have shown limited efficacy in neuroblastoma, with the best outcomes reported in patients with a low tumor burden, highlighting the need for further CAR optimization. One approach to addressing the high tumor burden involves engineering CAR T cells to release or express transgenic cytokines. However, its systemic toxicity remains an important therapeutic challenge. In this study, we evaluated the efficacy of IL15- and IL21-enhanced glypican 2 (GPC2)-targeted CAR T cells (GPC2-CAR T cells) in targeting high-burden neuroblastoma. Three strategies for expressing the cytokines were evaluated: constitutive secretion (GPC2-CAR + sol.IL15.IL21), constitutive membrane-tethered expression (GPC2-CAR + teth.IL15.IL21), and NFAT-inducible membrane-tethered expression (GPC2-CAR + NFAT.IL15.IL21). Engineered GPC2-CAR T cells were tested in vitro and in vivo using high neuroblastoma burden xenograft models. Additionally, single-cell RNA sequencing was used to profile the effector cells in the tumor microenvironment. All three versions of GPC2-CAR T cells significantly enhanced killing against a high neuroblastoma burden, both in vitro and in vivo, relative to control GPC2-CAR T cells. Mice treated with GPC2-CAR + NFAT.IL15.IL21 exhibited significantly lower anorexia-associated morbidity/mortality. Supporting these data, tumor-infiltrating GPC2-CAR + NFAT.IL15.IL21 developed an immunosuppressive transcriptional profile upon tumor regression, leading to prolonged survival in treated mice. In contrast, GPC2-CAR + teth.IL15.IL21 maintained a proinflammatory transcriptional signature despite near tumor clearance, resulting in hypercytokinemia and death. NFAT-inducible co-expression of tethered IL15/IL21 enhanced GPC2-CAR T-cell function against a high neuroblastoma burden with acceptable tolerability in mice. Further studies are required to validate these findings.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1363-1373"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12278764/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494728","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-derived EBI3 promotes CD8+ T cell exhaustion via STAT4-IL-10/CCL5 in gastric cancer.","authors":"Yong-Jia Yan, Xin Liu, Daohan Wang, Zexuan Shen, Wenxin Zhang, Zhaoxiong Zhang, Yangpu Jia, Peiyao Wang, Yuman Fong, Yanghee Woo, Weihua Fu","doi":"10.1158/2326-6066.CIR-24-1228","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1228","url":null,"abstract":"<p><p>Combination chemotherapy and immunotherapy are effective against advanced gastric cancer (GC). However, T cell exhaustion in the tumor microenvironment may decrease the immune response and compromise the effectiveness of immunotherapy. Herein, we report the potential role of EBI3 in promoting T cell exhaustion and its mechanism in GC, showing high expression of EBI3 in GC. Correlation analysis between EBI3 expression level and clinical-pathological features indicated significant associations with Tumor stage, Nodal staging, pathologic stage, and degree of tumor differentiation. EBI3 expression levels correlated with a state of high CD8+ T cell exhaustion, as identified by transcriptome sequencing and mice orthotopic GC models. On exposure to EBI3, CD8+ T cells showed signs of cell exhaustion as reduced cytokine secretion and increased expression of inhibitory receptors in vitro/vivo studies. Mechanistically, EBI3 induced T cell exhaustion by promoting phosphorylation of STAT4, upregulating the transcription of downstream target genes CCL5 and IL-10. An anti-EBI3 heptapeptide (Val-Tyr-Leu-His-Trp-His-Asp) was developed, which competitively bound EBI3 and reversed the induction of T cell exhaustion. Taken together, we identified a T cell exhaustion mechanism in GC via the EBI3-STAT4-IL10/CCL5 axis and developed an anti-EBI3 heptapeptide with an antagonistic function. These findings provide a potential immunotherapeutic target and support the development of EBI3-based interventions to enhance immunotherapy efficacy in GC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943996","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":"Tunneling CARs: Increasing CAR T-cell tumor infiltration through the overexpression of MMP-7 and Osteopontin-b.","authors":"Stacey Van Pelt, Mark White, Candise Tat, Devyn Hooper, Lindsay J Talbot, Mary Kathryn McKenna, Rohan Fernandes, Cliona M Rooney, Bilal Omer","doi":"10.1158/2326-6066.CIR-25-0149","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0149","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy against hematologic malignancies but has struggled to achieve comparable success in solid tumors. A key obstacle in solid tumors is the extracellular matrix (ECM), which impedes CAR T-cell infiltration. In clinical trials, neuroblastoma (NB) has shown responsiveness to GD2-directed CAR T-cell therapy, however, the failure of GD2.CAR T cells to effectively clear bulky disease - characterized by dense ECM - highlights the critical challenge of infiltration. In this study, we demonstrate that GD2.CAR T cells exhibit a unique infiltration-restriction compared to other CAR T cells and endogenous T cells. A separate analysis of clinical datasets identified MMP7 and SPP1 (which encodes osteopontin; OPN) as candidate genes to improve the infiltration of GD2.CAR T cells as these were upregulated in tumor-infiltrating leukocytes. MMP-7 and OPN overexpression enhanced CAR T-cell extravasation and interstitial movement in ECM-dense environments in vitro. Overexpression of either OPN or MMP-7 significantly improved tumor infiltration in a xenograft model of NB. This resulted in improved tumor control and a survival extension in OPN-GD2.CAR T-cell treated mice compared to unmodified GD2.CAR T cells. OPN overexpression did not increase off-target infiltration into healthy tissues or promote tumor metastasis, highlighting its potential for safe therapeutic application. Our study provides a framework for further exploration of gene modifications to improve CAR T-cell infiltration in solid tumors and identifies OPN as a candidate to explore in this regard.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144944048","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":"Chronic ISG15 Exposure Accelerates CD8+ T-cell Dysfunction while Increasing PD-1 Blockade Sensitivity in Oral Squamous Cell Carcinoma.","authors":"Yu-Lin Chen, Amir Yousif, Chung-Hsing Chen, Ava Lowin, Abbey A Saadey, Ssu-Han Wang, Shih Sheng Jiang, Ya-Wen Chen, Hazem E Ghoneim","doi":"10.1158/2326-6066.CIR-25-0047","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0047","url":null,"abstract":"<p><p>Immunotherapy has emerged as a promising treatment for head and neck squamous cell carcinoma (HNSCC), yet clinical responses remain limited. Elevated expression of interferon-stimulated gene 15 (ISG15), commonly observed in oral squamous cell carcinoma (OSCC), may contribute to this limited efficacy. Although chronic interferon signaling is known to impair CD8+ T cell function, the specific role of secreted ISG15 in T cell exhaustion remains unclear. Analysis of human OSCC datasets revealed significant enrichment of the ISG core score-including ISG15-in tumors compared to adjacent non-tumor tissues. Using a novel in vitro model of human T cell dysfunction, we found that acute ISG15 exposure enhances CD8+ T cell effector functions, whereas prolonged exposure induces severe dysfunction via a CD11a/LFA-1-independent, endocytosis-dependent mechanism. In an immunocompetent orthotopic OSCC model, ISG15-expressing tumors exhibited accelerated growth and recruited more tumor-reactive CD8+ T cells; however, these cells were functionally impaired. Importantly, PD-1 blockade treatment significantly slowed tumor progression and restored T cell function in ISG15-expressing tumors. Together, our findings reveal that chronic ISG15 exposure promotes CD8+ T cell dysfunction, but these cells remain responsive to PD-1 blockade. This study identifies ISG15 as a potential biomarker for identifying patients likely to benefit from PD-1 blockade therapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943937","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}