Cancer immunology research最新文献

{"title":"KRAS-G12C inhibition-induced enrichment of MHC-Ihigh immune-active tumor cells directs immune-effector TME development to augment therapeutic efficacy.","authors":"Mohammed L Ibrahim, Dana Foresman, Hong Zheng, Xiaoxian Liu, Mengyu Xie, Theresa A Boyle, Joseph O Johnson, Paulo C Rodriguez, Daniel Abate-Daga, Brian Ruffell, Alexander R Anderson, Eric B Haura, Xiaoqing Yu, Amer A Beg","doi":"10.1158/2326-6066.CIR-26-0213","DOIUrl":"10.1158/2326-6066.CIR-26-0213","url":null,"abstract":"<p><p>Inhibition of KRASG12C (G12Ci) has shown promising clinical activity in several cancers; however, emergence of resistance is a major limitation to long-term benefit. It remains unknown how G12Ci impacts the tumor immune microenvironment and its association with resistance. We investigated the immune modulatory impact of the G12Ci sotorasib in KrasG12C/Trp53-/- (KP) lung and colon carcinoma models. Single-cell RNA sequencing of tumors in both models demonstrated sotorasib-induced loss of proliferative tumor cells and to the enrichment of immune-active tumor cells with elevated NF-B and interferon signaling, and elevated MHC-I expression. These changes led to an increased proportion of effector T cells and MHC-IIhi macrophages in the tumors, and a reduced proportion of regulatory myeloid cells. Furthermore, sotorasib-resistant tumors exhibited a marked reduction of MHC-Ihigh immune-active tumor cells and immune cell type changes. Enrichment of immune-active tumor cells was associated directly with sotorasib-induced activation of NF-B and STAT1, leading to heightened responsiveness to inflammatory cytokines and to upregulation of MHC-I and chemokine expression. These findings indicate that modulation of immune-active tumor cell populations is a key mechanism associated with G12Ci therapeutic efficacy and the development of resistance.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944429","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":"Spatial statistics infer structured immune signatures in primary prostate cancer.","authors":"Ali Amiryousefi, Jeremiah Wala, Jia-Ren Lin, Brian William Labadie, Aishwarya Atmakuri, Zoltan Maliga, Eamon Toye, Kiranj Chaudagar, Madeleine S Torcasso, Shannon Coy, Giuseppe Nicolo Fanelli, Brigette Kobs, Fabio Socciarelli, Andréanne Gagné, Eliezer M Van Allen, Akash Patnaik, Peter Sorger","doi":"10.1158/2326-6066.CIR-26-0106","DOIUrl":"10.1158/2326-6066.CIR-26-0106","url":null,"abstract":"<p><p>The spatial arrangement of immune cells in the tumor microenvironment (TME) varies widely, from dispersed to clustered and tumor excluded to infiltrating. Multiplexed spatial profiling is an effective means of characterizing tumor-infiltrating lymphocytes (TILs) and immune complexes such as tertiary lymphoid structures (TLS) in the TME. However, few approaches have been described for objectively parametrizing patterns of immune organization and assessing their association with biological or clinical variables. This makes it difficult to evaluate whether a set of tumors is relatively immunologically cold or hot. Here we describe an intuitive set of statistical tools (available in the R package, tlsR) for characterizing lymphocyte patterns in the TME of solid cancers. We applied tlsR to primary prostate cancer (PCa), which is often described as immunologically 'cold'. Using a cohort of 29 radical prostatectomy specimens stratified into low Gleason-grade (LGG; n=15) and high Gleason-grades (HGG; n =14) we showed that HGG PCa is significantly more infiltrated than LGG PCa with lymphocytes organized into B cell or T cell enriched immune clusters (BICs and TICs). A subset of these ICs had the B and T cell zonation and follicular dendritic cells characteristic of a bona fide TLS. HGGs were also enriched with ICs containing precursor exhausted T cells (Tpex) and proliferating B cells and their tumor compartments harbor granzyme-B+ cytotoxic T cells in contact with cancer cells. Thus, far from being cold, a subset of HGG PCa has features associated with active immune surveillance, a finding with implications for emerging PCa immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148944444","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":"Leukocyte immunoglobulin-like receptor A3 inhibits the activity of immunosuppressive myeloid cells.","authors":"Meng Fang, Xing Yang, Jingjing Xie, Qi Lou, Chengcheng Zhang, Ryan Huang, Xiaoye Liu, Yubo He, A E M Adnan Khan, Cheryl M Lewis, Cheng Cheng Zhang","doi":"10.1158/2326-6066.CIR-26-0070","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0070","url":null,"abstract":"<p><p>Myeloid checkpoint blockade as monotherapy often yields limited benefit, suggesting that multiple inhibitory pathways cooperatively sustain myeloid immunosuppression in the tumor microenvironment (TME). However, strategies to concurrently target multiple myeloid checkpoints remain challenging. Leukocyte immunoglobulin-like receptor A3 (LILRA3) is a soluble LILRA/B family member with unclear immunoregulatory function. Here, we show that LILRA3 is significantly reduced in the serum and tumor tissues of cancer patients, and its systemic levels positively correlate with cytotoxic T cell infiltration and improved survival. LILRA3 suppresses immunosuppressive myeloid cells, enhances pro-inflammatory cytokine production, and inhibits M2 macrophage polarization, thereby indirectly promoting T cell proliferation. Mechanistically, LILRA3 binds to LILRB4 and multiple endogenous LILRB ligands, blocking downstream inhibitory signaling. LILRA3 restrains tumor growth in myeloid-specific LILRB2- and LILRB4-transgenic mice and in humanized mouse models. These findings identify LILRA3 as a natural multi-LILRB signaling antagonist that counteracts myeloid-driven immunosuppression and highlight its potential as a therapeutic immune modulator.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148918604","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":"Autologous Glypican-3-Targeted, Armored CAR T Cells in Patients with Advanced Solid Tumors: A Phase 1 Dose-Escalation Study of TAK-102.","authors":"Yasutoshi Kuboki, Takafumi Koyama, Masafumi Ikeda, Tomoyuki Satake, Takeshi Sawada, Yutaka Shimazu, Shunsuke Kondo, Yuki Katsuya, Hideaki Kagehara, Takenori Akaike, Aman Singh, Kondala Atkuri, Petar Pop-Damkov, Koji Tamada, Takako Eguchi Nakajima","doi":"10.1158/2326-6066.CIR-25-0855","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-0855","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapies have shown limited promise in solid tumors owing to the immunosuppressive tumor microenvironment. TAK-102 is a next-generation, glypican-3 (GPC3)-targeted CAR T-cell therapy engineered to co-express interleukin-7 (IL-7) and chemokine ligand 19 (CCL19), enhancing T-cell survival and trafficking. In this first-in-human, open-label, phase 1, dose-escalation study (ClinicalTrials.gov: NCT04405778), we evaluated a single TAK-102 infusion in 11 patients with GPC3+ advanced solid tumors refractory or intolerant to standard therapies. Patients received TAK-102 at one of three dose levels following leukapheresis and lymphodepletion chemotherapy. The primary endpoints were the incidences of dose-limiting toxicities, treatment-emergent adverse events, and adverse events of special interest. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were hematologic, including neutropenia and leukopenia (81.8%), and cytokine release syndrome (54.5%), all grade 1-2. No objective responses were observed; however, five patients achieved stable disease (disease control rate, 45.5%). One patient had a 26.1% reduction in tumor size lasting 9 months, accompanied by a 51.6% decline in serum alpha-fetoprotein. Cellular kinetics showed dose-dependent expansion, with the highest exposure at 5 × 10⁸ CAR+ cells/body. Post-treatment biopsies revealed increased CD8+ T-cell infiltration and activation markers, although CAR+ cells were undetectable in tumor tissue. Serum CCL19 levels increased with dose, suggesting immune priming. These findings support a manageable safety profile for TAK-102 and provide early evidence of biological activity in solid tumors. Further studies are warranted to optimize dosing, improve CAR T-cell persistence, and evaluate efficacy in larger patient cohorts.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148910960","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":"The post-transcriptional regulator HuR promotes immune evasion in pancreatic ductal adenocarcinoma.","authors":"Yifei Guo, Jennifer M Finan, Alexandra Q Bartlett, Katherine R Pelz, Shamilene Sivagnanam, Katie E Blise, Nell Kirchberger, Konjit Betre, Yuhui Wei, Jennifer R Eng, Vidhi M Shah, Koei Chin, Grace A McCarthy, Hen Halamish, Kevin MacPherson-Hawthorne, Colin J Daniel, Canping Chen, Aaron J Grossberg, Zheng Xia, Sha Cao, Lisa M Coussens, Rosalie C Sears, Jonathan R Brody, Robert Eil","doi":"10.1158/2326-6066.CIR-26-0472","DOIUrl":"10.1158/2326-6066.CIR-26-0472","url":null,"abstract":"<p><p>The tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) is characterized by restrained function of effector T cells that drives resistance to immunotherapy. While tumor-extrinsic stroma and myeloid cells have been shown to mediate PDAC immune evasion, the role of tumor-intrinsic post-transcriptional gene regulation in driving tumor-immune crosstalk has been relatively unexplored. Here, we report that the RNA-binding protein HuR (ELAVL1) is enriched in human PDAC and negatively correlates with T-cell infiltration. In two immunocompetent, murine models of PDAC, we found that genetic disruption of HuR impaired tumor growth without significantly impacting in vivo proliferation. Comprehensive spatial and flow cytometry profiling of the PDAC TME revealed that genetic disruption of HuR in PDAC enhanced both T-cell number and functional state. Moreover, T-cell depletion abrogated the growth difference caused by HuR loss. Mechanistically, RNA immunoprecipitation sequencing, single-cell RNA sequencing, and orthogonal functional assays in vitro and in vivo showed that HuR stabilized mTOR pathway transcripts critical for metabolic adaptation in PDAC. HuR-driven metabolic reprogramming promoted tumor nutrient dominance and limited nutrient consumption by neighboring tumor-reactive T cells. Accordingly, HuR depletion sensitized PDAC tumors to immune checkpoint blockade and allowed for the expansion of tumor-specific T-cell populations, suggesting that HuR-mediated nutrient dominance and immune evasion have translational relevancy. Overall, we found that the post-transcriptional regulator HuR facilitates immune evasion in PDAC by constraining T-cell function, identifying HuR blockade as a promising therapeutic strategy in combination with immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891231","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":"Enhancement of Ferroptosis in Escape Variant Tumor Cells by IFNγ Derived from Antigen-Specific T Cells Controls Tumor with Heterogeneity.","authors":"Daisuke Ehara, Kiyoshi Yasui, Mitsuhiro Yoneda, Daisuke Muraoka, Situo Deng, Pengyu Miao, Chenxu Jiang, Huimin Sun, Sachiko Okamoto, Yasunori Amaishi, Hiroyuki Murota, Hiroaki Ikeda","doi":"10.1158/2326-6066.CIR-25-0175","DOIUrl":"10.1158/2326-6066.CIR-25-0175","url":null,"abstract":"<p><p>Tumor masses often exhibit heterogeneity, including escape variant clones that lack antigen-presenting machinery and/or tumor antigens, which poses a major challenge to immunotherapy. Ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, has been shown to effectively induce cell death in various tumor cells. Recent studies have reported that IFNγ suppresses the expression of system Xc-, thereby enhancing the induction of ferroptosis. Based on this, we hypothesized that combining immunotherapy with ferroptosis inducers could enhance antitumor effects against both antigen-positive and antigen-negative tumor cells. We found that combining RSL3, a ferroptosis inducer, with MART-1-specific T-cell receptor-engineered T cells eradicates a heterogeneous tumor model consisting of human melanoma cells and their β2-microglobulin knockout counterparts. In NOD.Cg-PrkdcscidIl2rgtm1Sug/ShiJic mice, this combination therapy demonstrates a significant antitumor effect against tumors with heterogeneity. These findings suggest that integrating ferroptosis inducers with immunotherapy could overcome the limitations imposed by escape-variant tumor clones, offering a promising strategy for cancer treatment.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1454-1466"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374681","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":"Peripheral Th17 Immune Signature Associates with Excellent Response to Anti-PD-1/Anti-PD-L1 Therapy across Solid Tumors.","authors":"Howard L Li, Soren Charmsaz, Chester Kao, Carlotta Pazzi, Madelena Brancati, James M Leatherman, Luke X Zhao, Waqar Arif, Royce P Lee, Jeric Hernandez, Nicole E Gross, Caroline Ellis, Christopher Thoburn, Yasser Ged, Jeannie Hoffman-Censits, Evan J Lipson, Marina Baretti, G Scott Chandler, Rajat Mohindra, Laura Tang, Sanjay Bansal, Aditi Guha, Elizabeth M Jaffee, Daniel J Zabransky, Won J Ho, Mark Yarchoan, Mari Nakazawa","doi":"10.1158/2326-6066.CIR-25-1611","DOIUrl":"10.1158/2326-6066.CIR-25-1611","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICI) have transformed cancer care, at times generating durable partial response (PR) or even complete response (CR) in advanced cancers. However, only a minority of patients experience these \"excellent\" responses. Thus, there is a need for novel biomarkers that can identify those with robust clinical benefit. To address this, we prospectively collected blood samples from 124 patients with advanced and/or metastatic pan-solid tumors treated as standard of care with anti-PD-1 or anti-PD-L1 alone or in combination with other agents. In this cohort, 30 of 124 (24.2%) patients were classified as excellent responders (ER), defined as experiencing a CR or a durable PR with progression-free survival (PFS) ≥1 year. Peripheral immune cells were analyzed by cytometry by time of flight, and cytokines were analyzed using a multiplex immunoassay. At baseline and early-on-treatment, ERs had elevated concentrations of Th17-associated cytokines, IL17F, IL21, and IL23 and decreased IL8 compared with non-ERs (P < 0.05). Elevated on-treatment IL6 was also associated with non-ERs (P < 0.05). High baseline IL17F and IL23 were associated with superior PFS, and high baseline IL8 was associated with inferior overall survival (P < 0.05). Non-ERs demonstrated decreased proportions of Th17 cells from baseline to early-on-treatment. Regression analysis of functional markers in non-ERs showed a proliferation of exhaustion-like Th17 cells (Ki67+TIGIT+) from baseline to early-on-treatment (P < 0.01) that was not present in ERs. This study identifies the Th17 pathway as a potential correlate of excellent ICI response and represents a comprehensive exploration of peripheral immune signatures associated with durable ICI benefit.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1484-1495"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148337881","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":"CAR T Cells Targeting O-Glycosylated Fibronectin Exhibit Potent Cytolytic Activity and Combine with Tumoral Toll-Like Receptor Agonism to Overcome Tumor Resistance.","authors":"Tiffany R King-Peoples, John T Keane, Hyeon-Gyu S Lewis, Fang Liu, Shawna K Brookens, Oula K Dagher, Kalpana Parvathaneni, Brittany L Gardner, Amal Ahmed, Emma E Furth, Priti Lal, Avery D Posey","doi":"10.1158/2326-6066.CIR-26-0009","DOIUrl":"10.1158/2326-6066.CIR-26-0009","url":null,"abstract":"<p><p>Tumors remodel the extracellular matrix (ECM) and glycosylation, yielding epitopes with restricted or limited detectability in normal adult tissues. In this study, we evaluated the O-glycosylated type III connecting segment domain of fibronectin (Tn-FN) as a chimeric antigen receptor (CAR) T-cell target. FDC6-BBζ CAR T cells recognizing Tn-FN were benchmarked against extra domain B-FN-targeted L19-BBζ and Tn-MUC1-targeted 5E5-BBζ. FDC6-BBζ mediated robust, antigen-dependent activation and cytotoxicity, outperforming L19-BBζ and matching 5E5-BBζ in vitro and in NOD/SCID gamma xenografts of prostate cancer. FDC6-BBζ and 5E5-BBζ CAR T cells achieved durable tumor control with increased intratumoral CD3+ infiltration and reduced tumor-collagen overlap. Cytotoxicity required an intact tumor IFNγ receptor 1 (IFNγR1); L19-BBζ further depended on Fas, whereas FDC6-BBζ and 5E5-BBζ were less Fas-dependent. Tumoral Toll-like receptor (TLR) 2/6 or TLR4 agonism restored FDC6-BBζ killing of IFNγR1-deficient targets and induced broad inflammatory and stress-response programs. Pharmacologic perturbation implicated caspase-dependent mechanisms and a contribution from inflammasome-linked signaling, whereas ferroptosis blockade did not abrogate restored killing. These findings establish Tn-FN as a glycoform-restricted, ECM-derived CAR target and show that innate agonists can reprogram tumor state to overcome resistance from impaired IFNγ signaling.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1400-1415"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13488855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374660","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":"VISTA+ Neutrophils Contribute to Platinum Resistance by Suppressing CD8+ T Cells in High-Grade Serous Ovarian Cancer.","authors":"Chuying Huo, Xibo Zhao, Dongdong Ye, Shaodan Lin, Dongdong Xu, Suen Wai Pang, Miaochun Xu, Junting Chen, Chunxian Huang, Yunyun Liu, Aoshuang Cheng, Lingjie Yang, Zhongqiu Lin, Lijuan Wang, Bowen Li, Huaiwu Lu","doi":"10.1158/2326-6066.CIR-25-1118","DOIUrl":"10.1158/2326-6066.CIR-25-1118","url":null,"abstract":"<p><p>Elevated neutrophil-to-lymphocyte ratio (NLR) has been associated with platinum resistance and poor outcomes in high-grade serous ovarian cancer (HGSOC), but the biological basis of this association remains unclear. We retrospectively analyzed 434 patients with HGSOC treated with platinum-based chemotherapy and found that elevated NLR was an independent predictor of platinum resistance. To further investigate the cellular basis of this association, we performed immunohistochemistry (IHC), proteomic profiling, and single-cell RNA sequencing on patient samples. These analyses identified a distinct subpopulation of V-domain immunoglobulin suppressor of T-cell activation-positive neutrophils (VISTA+Neus) enriched in resistant tumors. High VISTA+Neus density was linked to shorter progression-free survival and showed greater predictive value for resistance than total neutrophils. Spatial and multicolor IHC analyses further showed that VISTA+Neus were associated with reduced CD8+ T-cell infiltration and cytotoxic features. Functional validation in an immunocompetent mouse model showed that anti-VISTA plus cisplatin reduced tumor growth, decreased neutrophil abundance, and increased CD8+ T-cell infiltration and granzyme B expression. CD8+ T-cell depletion markedly attenuated the therapeutic benefit of the combination. These findings support VISTA+Neus as a potential immunosuppressive neutrophil subset associated with platinum resistance and CD8+ T-cell suppression in HGSO, and support further investigation of VISTA-targeted strategies and the potential biomarker value of VISTA+Neus.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1510-1527"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535324/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367177","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":"Topical Resiquimod Elicits Systemic Protection and Improves Anti-PD-1 Therapy in Melanoma via Priming of CD8+ T Cells.","authors":"Shujing Liu, Alain H Rook, Alexander C Huang, Amit Maity, Zhiyuan Qin, Yeqing Chen, Delu Song, Yanxiang Deng, Zhi Huang, Giorgos C Karakousis, Tara C Mitchell, Ravi K Amaravadi, Lynn M Schuchter, Zev A Binder, Donald M O'Rourke, Meenhard Herlyn, Wei Guo, Xiaowei Xu","doi":"10.1158/2326-6066.CIR-25-0998","DOIUrl":"10.1158/2326-6066.CIR-25-0998","url":null,"abstract":"<p><p>The Toll-like receptor (TLR) 7/8 agonist resiquimod shows promise for treating cutaneous T-cell lymphoma and actinic keratosis, yet its mechanism of action remains unclear. We demonstrated that topical resiquimod significantly inhibited melanoma growth across various genetic and syngeneic mouse models, prolonged survival, and reduced lymph node metastasis in vivo. Resiquimod suppressed B16 melanoma growth, with an effect superior to that of imiquimod. The therapeutic effect was CD8+ T cell-dependent, as evidenced by the loss of efficacy upon CD8+ T-cell depletion or in Rag2-/- mice. Resiquimod increased intratumoral CD45+ inflammatory cells, particularly antigen-experienced PD-1+CD62L-CD8+ effector T cells, and enhanced their Ki-67 and granzyme B expression. Resiquimod significantly expanded Pmel- and Trp2-specific CD8+ T cells in the presence of dendritic cells (DC). Topical treatment of melanoma-bearing mice induced systemic protection in rechallenge experiments. In addition, combining topical resiquimod with anti-PD-1 antibodies led to superior inhibition of tumor growth and metastasis across multiple melanoma models. Proteomic analysis revealed increased granzyme B and CD26 and decreased phosphorylated FOXO3a after treatment. In patient-derived organoids and melanoma slice cultures, resiquimod induced significant tumor killing and CD8+ T-cell activation, further augmented by PD-1 antibodies. Our findings support the conclusion that resiquimod promotes CD8+ T-cell priming via DCs and enhances the therapeutic efficacy of anti-PD-1 checkpoint blockade in melanoma.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1496-1509"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148223220","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}