Cancer immunology research最新文献

{"title":"Liver metastases license neutrophils through IL-1 to potentiate cancer progression.","authors":"Ashley N Pearson, Jessica Waninger, Amanda K Huber, Erin A Holcomb, Jadyn G James, Justine Kyi, Ameer L Elaimy, Zhuwen Wang, Emily L Lasse Opsahl, Shuvasree SenGupta, David A Elliott, Enid Choi, Qiang Zhang, Meredith A Morgan, Daniel T Chang, Theodore S Lawrence, Adam Courtney, Yatrik M Shah, Jason S Knight, Marina Pasca di Magliano, Shinjae Yoo, Silvia Crivelli, Carole A Parent, Nithya Ramnath, Alex K Bryant, Weiping Zou, Michael D Green","doi":"10.1158/2326-6066.CIR-24-1074","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-24-1074","url":null,"abstract":"<p><p>Liver metastases are associated with poor cancer outcomes in many solid malignancies, but the factors influencing the trajectory of patients with liver metastases are poorly defined. It is known that liver metastases suppress systemic antitumor immunity; however, the underlying mechanisms remain incompletely described. We report that liver metastases promote disease progression in patients and preclinical models. Patients with liver metastases progress rapidly, regardless of primary tumor type. In multiple murine models, we find that liver metastases potentiate neutrophil migration and activity. Neutrophils licensed by liver metastasis augment metastatic colonization in an IL-1 dependent manner. Thus, liver metastasis rewires systemic immunity to promote cancer progression. This work has implications for treatment strategies to address the poor clinical outcomes associated with liver metastasis.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999749","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":"DUSP11 is an intracellular innate immune checkpoint in lung adenocarcinoma.","authors":"Brian J Thomas, Xue Bai, Benjamin J Cryer, Sydney M Escobar, Lee-Ann H Allen, Mark A Daniels, Margaret J Lange, Donald H Burke","doi":"10.1158/2326-6066.CIR-25-0086","DOIUrl":"10.1158/2326-6066.CIR-25-0086","url":null,"abstract":"<p><p>The discovery of immune checkpoints and the rapid growth of immuno-oncology (IO) have sparked efforts to utilize the immune system to treat a wide range of cancer types/subtypes. While the major focus of IO over the past decades has been to manipulate the adaptive immune system, recent attention has been given to manipulating the innate immune system to treat cancer and/or to enhance adaptive responses. Here, we detailed the intracellular protein, Dual Specificity Phosphatase 11 (DUSP11), as an innate immune checkpoint (iIC) in Non-Small Cell Lung Cancer (NSCLC) adenocarcinoma (LUAD). Expression of this atypical phosphatase was correlated with patient survival for multiple cancer types, and we reported here that its activity was important for the viability of lung cancer cells in vitro. Specifically, we demonstrated that DUSP11 knockdown in LUAD cells induces apoptosis and an innate immune response capable of activating other cells in vitro, and we provided evidence that these phenotypes are primarily mediated by the pattern recognition receptor, retinoic acid inducible gene I (RIG-I). Finally, we showed that expression of DUSP11 was important for tumor engraftment and growth of human LUAD in mice. Overall, these data are the first to establish DUSP11 as an immunosuppressive, pro-neoplastic, and potentially targetable protein in LUAD. In addition, our data suggests that the anti-cancer mechanisms induced by diminishing the activity of DUSP11 are likely to be generalizable to other cancer types such as breast and skin cancer, warranting future investigation and highlighting therapeutic potential.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":8.2,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144999703","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":"Bicistronic CAR T Cell against BCMA and CD229 Effectively Controls Myeloma Even When BCMA Expression Is Limited.","authors":"Luis Gerardo Rodríguez-Lobato, Oriol Cardús, Joan Mañé-Pujol, Anthony M Battram, Sergi Vaqué-Salsench, Judith Carpio, Lorena Pérez-Amill, Hugo Calderón, Beatriz Martín-Antonio, Aina Oliver-Caldés, Ester Lozano, David F Moreno, Valentin Ortiz-Maldonado, Maria Queralt Salas, Anna de Daniel, Natalia Tovar, M Teresa Cibeira, Laura Rosiñol, Joan Bladé, Manel Juan, Álvaro Urbano-Ispizua, Pablo Engel, Carlos Fernández de Larrea","doi":"10.1158/2326-6066.CIR-24-1313","DOIUrl":"10.1158/2326-6066.CIR-24-1313","url":null,"abstract":"<p><p>Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy has revolutionized the prognosis of patients with relapsed/refractory multiple myeloma. Regrettably, despite unprecedented overall response rates achieved with this approach, most patients eventually relapse. One of the primary reasons for this is the complete loss or reduced expression of BCMA on the malignant plasma cell surface. Consequently, new therapeutic targets are under investigation. Another potential therapeutic approach involves the use of CAR T cells targeting two tumor antigens. In this study, we developed and validated a monospecific CAR targeting CD229, which was effective in in vitro and in vivo NOD.Cg-Prkdcscid Il2rdtm1Wjl/SzJ mouse models with both homogeneous and heterogeneous BCMA expression. Additionally, we created a bicistronic CAR T cell targeting both CD229 and BCMA, which demonstrated efficacy in models with homogeneous BCMA expression, in heterogeneous models featuring small clonal populations with biallelic BCMA deletion, and in cases with reduced BCMA expression both in vivo and in vitro. Regarding \"on-target off-tumor toxicity,\" no fratricide was observed among CAR T cells, but there was a limited elimination of nonactivated T cells. The immune pressure exerted by anti-CD229 CAR T cells led to the loss of the CD229 antigen expression in some instances. In summary, this work underscores the potential utility of CD229 alone or in combination with BCMA as an immunotherapeutic target in multiple myeloma, especially in cases marked by diminished or absent BCMA expression.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1374-1390"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504896","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":"In Vivo Labeling Resolves Distinct Temporal, Spatial, and Functional Properties of Tumor Macrophages and Identifies Subset-Specific Effects of PD-L1 Blockade.","authors":"Colin Y C Lee, Isaac Dean, Nathan Richoz, Zhi Li, Bethany C Kennedy, Lisa A Vettore, Youhani Samarakoon, Kathryn L Gilroy, Tetsuo Hasegawa, Gianluca Carlesso, Scott A Hammond, Simon J Dovedi, Owen J Sansom, Zewen K Tuong, Timotheus Y F Halim, David R Withers, Menna R Clatworthy","doi":"10.1158/2326-6066.CIR-24-1233","DOIUrl":"10.1158/2326-6066.CIR-24-1233","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAM) are a universal feature of cancers but variably influence outcomes and treatment responses. In this study, we used a photoconvertible mouse to distinguish newly entering, monocyte-derived TAMs (mdTAM) that were enriched at the tumor core from resident-like TAMs that localized with fibroblasts at the tumor-normal interface. The mdTAM pool was highly dynamic and continually replenished by circulating monocytes. Upon tumor entry, these monocytes differentiated down two divergent fate trajectories distinguished by the expression of MHC class II. MHC-II+ mdTAMs were functionally distinct from MHC-II- mdTAMs, demonstrating increased capacity for endocytosis and Fc-gamma receptor-mediated phagocytosis, as well as proinflammatory cytokine production. Both mdTAM subsets showed reduced expression of inflammatory transcripts and increased expression of PD-L1 with increasing tumor dwell time. Treatment with anti-PD-L1 skewed mdTAM differentiation toward the MHC-II+ fate and attenuated the anti-inflammatory effects of the tumor environment. Anti-PD-L1 enhanced mdTAM-CD4+ T cell interactions, establishing an IFNγ-CXCL9/10-dependent positive feedback loop. Altogether, these data resolve distinct temporal, spatial, and functional properties of TAMs and provide evidence of subset-specific effects of PD-L1 blockade.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1453-1470"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617970/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309574","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":"Discovery of BMS-986408, a First-In-Class Dual DGKα and DGKζ Inhibitor that Unleashes PD-1 Checkpoint and CAR T-cell Immunotherapies.","authors":"Michael Wichroski, Si-Qi Liu, Lauren M Zasadil, Joseph L Benci, Patrick C Gedeon, Kendall J Condon, Suhasini Joshi, Shana Posy, Patrick Carlson, Alison Maier, Jiao Shen, Rakeeb Kureshi, Yuka Amako, Tai Wang, Ryan L Powles, Yanyun Li, Tho Lai, Igor Katsyv, Hongchen Qiu, Huilin Qi, Jessica Wong, Dandan Zhao, Dana Banas, Joelle Onorato, Gregory Locke, Xueer Chen, Wen-Chi Chou, Erica Cook, Abigail E Witt, Christopher M Barbieri, Hong Zhang, Jonathan B Olsen, Alba Font Tello, Eugene Drokhlyansky, Denise C Grünenfelder, Louis Chupak, Tyler A Longmire, Jon C Jones, Travis J Hollmann, David G Kugler, John N Feder, Raphael Bueno, John Wain, Pallavur Sivakumar, Yu Liu, Stephanie K Dougan, Cloud P Paweletz, David A Barbie, Emma Lees","doi":"10.1158/2326-6066.CIR-25-0156","DOIUrl":"10.1158/2326-6066.CIR-25-0156","url":null,"abstract":"<p><p>Diacylglycerol kinase α (DGKα) and DGKζ are lipid kinases that negatively regulate T-cell signaling through diacylglycerol metabolism, making them attractive targets for next-generation immunotherapy. In this study, we report the discovery and preclinical characterization of the clinical-stage DGKα and DGKζ lipid kinase inhibitor, BMS-986408. BMS-986408 binds to the accessory subdomain of the catalytic domain and inhibits DGKα/ζ through a mechanism of action that includes competitive inhibition for the diacylglycerol substrate, subcellular translocation to the plasma membrane, and proteosome-dependent degradation. DGKα/ζ inhibition markedly improved the therapeutic benefit of PD-1 therapy by unleashing T-cell responses in the tumor while also amplifying the priming and expansion of tumor-reactive T cells in tumor-draining lymph nodes. Simultaneous inhibition of both DGKα and DGKζ was required to maximize combination benefit with PD-1 therapy. Furthermore, we observed in non-small cell lung cancer (NSCLC) patient samples that DGKα and DGKζ were broadly expressed in tumor-infiltrated T cells and that combination therapy invigorated a robust cytokine response in organotypic tumors derived from patients with NSCLC, supporting the clinical evaluation of this combination in patients with NSCLC. BMS-986408 also markedly improved CD19-targeted CAR T-cell therapy efficacy by overcoming hypofunctionality, insufficient expansion, and lack of costimulatory ligands. BMS-986408 represents a critical step toward evaluating the broad immunotherapy potential of DGKα/ζ inhibitors in patients with cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1342-1362"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12402804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282447","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":"SF3B1K700E Neoantigen Is a CD8+ T-cell Target Shared across Human Myeloid Neoplasms.","authors":"Melinda A Biernacki, Jessica Lok, Kimberly A Foster, Carrie Cummings, Stephanie Busch, R Graeme Black, Suhita Ray, Laura Baquero Galvis, Tim Monahan, Stephen T Oh, Vivian G Oehler, Derek L Stirewalt, David Wu, H Joachim Deeg, Sergei Doulatov, Marie Bleakley","doi":"10.1158/2326-6066.CIR-24-0091","DOIUrl":"10.1158/2326-6066.CIR-24-0091","url":null,"abstract":"<p><p>Acquired mutations in spliceosome genes in early hematopoietic stem/progenitor cells are common events in myelodysplastic neoplasms (MDS) and related myeloid malignancies. Mutations in the spliceosome factor subunit B1 (SF3B1) gene occur in ≥20% of MDS cases at conserved hotspots and in early neoplastic clones as driver events. Neoantigens from aberrant SF3B1 proteins could serve as shared T-cell therapy targets for SF3B1-mutated myeloid neoplasms. We identified a candidate neoantigen from the prevalent SF3B1K700E variant using in silico predictions of epitope processing and presentation and then validated presentation and immunogenicity in vitro. CD8+ T cells recognizing SF3B1K700E demonstrated high functional avidity and killed neoplastic myeloid cell lines and primary cells in an antigen-specific manner. We then sequenced, cloned, and transduced an SF3B1K700E-specific T-cell receptor into third-party T cells and confirmed that T-cell receptor transfer conferred antigen specificity and killing of neoplastic myeloid cells in vitro and in vivo. The data indicate that the SF3B1K700E neoantigen represents a promising T-cell target for patients with SF3B1-mutated MDS and acute myeloid leukemia.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1391-1404"},"PeriodicalIF":8.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494729","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":"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}