Cancer immunology research最新文献

{"title":"Tim-3 Sustains Tumor Treg Stability and Function, Limiting Checkpoint Blockade Therapy Efficacy.","authors":"Hridesh Banerjee, Onyedikachi V Onyekachi, Hector Nieves-Rosado, Benjamin M Murter, Aditi Kulkarni, Surya P Pandey, Edgar Cardona, Josephine E Dougherty, Housaiyin Li, Pragati Upadhyay, Reinhard Hinterleitner, Robert L Ferris, Lawrence P Kane","doi":"10.1158/2326-6066.CIR-25-0687","DOIUrl":"10.1158/2326-6066.CIR-25-0687","url":null,"abstract":"<p><p>Regulatory T cells (Treg) act as a powerful barrier to effective antitumor immunity. Although manipulating Treg is a promising anticancer strategy, doing so while sparing general immune tolerance has been a challenge. Identifying factors specifically expressed in tumor-infiltrating Treg is therefore important for better understanding cancer pathogenesis and identifying novel therapeutic targets that enhance antitumor immunity. We show that T-cell immunoglobulin and mucin 3 (Tim-3) expression on tumor Treg is required for the function and survival of these cells, in part through Akt and FOXO1 signaling. Deleting Tim-3 in Treg leads to delayed tumor-specific T-cell exhaustion and lower tumor burden, without altering peripheral homeostasis. Similar effects were noted when Tim-3 was only deleted from half of the Treg or when deletion was delayed until after tumor inoculation. Moreover, Treg-specific deletion of Tim-3 cooperated with PD-1 checkpoint blockade to sensitize an immunotherapy-resistant tumor model. In addition, a decrease in Tim-3+ tumor Treg correlated with responsiveness to PD-1/LAG-3 combination checkpoint blockade in a human clinical trial. Overall, our data provide evidence that Tim-3-expressing Treg are a promising target to modulate tumor-specific immune responses.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1620-1634"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444609","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 Vitro Inhibition of STAT5 Signaling Limits CD8+ T-cell Exhaustion and Improves Outcomes in Adoptive T-cell Therapy.","authors":"Mitra Shourian, Benoîte Bourdin, Nehme El-Hachem, Clémence Ruisseaux, Alexis Vallée, Arnau Ballestero Vidal, Olivier Gingras, Hugo Roméro, Edward O Kwarteng, Élie Haddad, Vincent-Philippe Lavallée, Jean-Christophe Beltra, Hélène Decaluwe","doi":"10.1158/2326-6066.CIR-25-1493","DOIUrl":"10.1158/2326-6066.CIR-25-1493","url":null,"abstract":"<p><p>T-cell exhaustion remains a barrier to adoptive cell therapies. Although γc cytokines are used to expand T cells, their impact on T-cell states remains incompletely defined. Using an in vitro model of repetitive T-cell receptor stimulation, we found that high-dose interleukin 2 (IL2) or IL15 promoted exhausted CD8+ T-cell (TEX) differentiation, with increased inhibitory receptor expression and loss of stem-like features. During chronic lymphocytic choriomeningitis virus clone 13 infection, high IL2Rβ expression marked virus-specific CD8+ T cells with features of terminally exhausted T cells, whereas IL2Rβ deficiency favored progenitor-like populations. In TEX, IL2 and IL15 preferentially induced STAT5 phosphorylation over other signaling pathways. Genetic disruption of STAT5 similarly supported progenitor subsets, implicating STAT5 in the progression toward more differentiated TEX states under chronic stimulation. We therefore asked whether transient STAT5 attenuation during in vitro T-cell expansion could bias differentiation toward progenitor-like populations without compromising functional competence. Transient JAK3 or STAT5 inhibition enriched TCF1+Ly108+ progenitor-like cells while preserving cytokine production and degranulation capacity. Following transfer into tumor-bearing mice, cells expanded under STAT5-inhibited conditions mediated superior tumor control and prolonged survival. Likewise, transient STAT5 inhibition preserved memory-progenitor phenotypes in human CD22 chimeric antigen receptor T cells without impairing cytotoxicity. RNA sequencing of STAT5 inhibitor-expanded CD8+ T cells confirmed reinforced stem-like transcriptional programs and reduced enrichment of effector and exhausted signatures. Together, these findings identify the IL2Rβ-STAT5 axis as a regulator of CD8+ T-cell differentiation and support transient STAT5 modulation during ex vivo expansion to improve therapeutic T-cell products.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1587-1603"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.","authors":"","doi":"10.1158/2326-6066.CIR-14-10-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-14-10-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"14 10","pages":"1535"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104463","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":"Periductal Fibroblast Density Defines Lymphocyte Exclusion via a CD44-Dependent Stromal Checkpoint in Pancreatic Cancer.","authors":"Zoe X Malchiodi, Alexander A Lekan, Robert K Suter, Atul Deshpande, Selime Arslan, Annabel J Lee, Nuan Wang, Ivana Peran, Brent T Harris, Anju Duttargi, Min-Ju Chien, Samika Hariharan, Lucia Wetherill, Sandra A Jablonski, Won Jin Ho, Marwa Afifi, Elana J Fertig, Louis M Weiner","doi":"10.1158/2326-6066.CIR-25-1481","DOIUrl":"10.1158/2326-6066.CIR-25-1481","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) exhibits dense fibrosis and immune exclusion. Although fibrosis has been studied globally and at the region-of-interest level, its impact on stromal-ductal architecture and immune cell localization remains unknown. In this study, we establish cancer-associated fibroblast (CAF)-stratified ductal spatial architecture as a fundamental determinant of immune exclusion in PDAC. Focusing on malignant PDAC epithelial ductal regions, the critical interface in which immune cells must access tumor epithelium, we demonstrate that periductal fibroblast organization dictates leukocyte proximity. Through integrative analysis of treatment-naïve patient samples from three independent cohorts-including imaging mass cytometry, multiplex immunohistochemistry, and single-cell RNA sequencing-we uncover that activated, proinflammatory leukocytes preferentially localize near malignant ducts in regions with low fibroblast density. Stratifying epithelial ductal regions by CAF abundance reveals a graded constraint: increasing fibroblast content corresponds to reduced leukocyte-epithelial proximity and elevated collagen I deposition. Despite their exclusion in high-CAF ducts, leukocytes in low-CAF ducts retain functional competence. Mechanistically, ligand-receptor inference implicates collagen-CD44 signaling as an adhesion axis anchoring immune cells within fibroblast-rich zones. CD44 blockade augments natural killer cell motility in vitro, whereas enhancing lymphocyte collagenase activity through matrix metalloproteinase 14 (MMP14) overexpression promotes infiltration by overcoming alpha smooth muscle actin (αSMA+) CAF-mediated stromal barriers in vivo. Thus, by establishing ductal regions as critical spatial units of immune exclusion, these findings provide a framework for dissecting stromal-immune interactions, reveal targetable \"stromal checkpoints,\" and provide complementary strategies to overcome CAF-driven barriers to leukocyte motility and infiltration in PDAC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1538-1552"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13485397/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Patient-Derived Screen Identifies HDAC Inhibitors as Enhancers of Phagocytosis and Potent Immunotherapy Partners.","authors":"Mona Khalaj, Andrew T Burden, Madison L Gutierrez, Sophia C Hoonsbeen, Parisa Nejad, Tal Raveh, Jacob S Young, Faranak Fattahi, Irving L Weissman","doi":"10.1158/2326-6066.CIR-25-0506","DOIUrl":"10.1158/2326-6066.CIR-25-0506","url":null,"abstract":"<p><p>Glioblastoma multiforme (GBM) is a lethal brain tumor with limited treatment options. Tumor-associated macrophages and microglia (TAM) drive immune suppression and tumor progression, making them a key therapeutic target for GBM. Enhancing TAM phagocytosis in GBM has shown promise, particularly with innate checkpoint inhibitors, such as CD47-blocking antibodies. However, small-molecule approaches, which offer tunable and potentially synergistic mechanisms, remain underexplored in this context. In this study, we conducted a large-scale small-molecule screen on primary TAMs isolated directly from tumors of patients with GBM, testing 1,365 compounds to identify drugs that enhance TAM phagocytosis. This screen revealed enrichment for histone deacetylase (HDAC)-targeting drugs among the top hits. HDAC inhibitors enhanced phagocytosis of cancer cells across multiple primary human TAM-GBM combinations and synergized with CD47 blockade ex vivo. In a xenograft GBM model, pracinostat suppressed tumor growth and extended survival, with additive benefit when combined with CD47 antibodies. RNA sequencing and H3K27Ac cleavage under targets and tagmentation profiling of pracinostat-treated TAMs in vivo revealed a two-tier mechanism: transcriptional reprogramming toward a proinflammatory state via NF-κB activation and epigenetic priming of FcγR-mediated phagocytic machinery, providing a mechanistic basis for the observed synergy with CD47 blockade. Our findings establish a patient-first functional screening platform for identifying TAM reprogramming therapeutics in GBM, validate HDAC inhibitors as a lead class that potentiates innate checkpoint immunotherapy, and provide additional candidate compounds for clinical investigation.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1685-1700"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435185","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":"Elevated CHAF1A Suppresses Type I Interferon Production and Causes Immunotherapy Resistance in Esophageal Squamous Cell Carcinoma.","authors":"Yue Ma, Mengde Shi, Ming Ma, Siru Li, Nana Cui, Yingjue Li, Tianjiao Dang, Rui Yang, Yang Bai, Bojun Wang, Chunhui Zhang, Chao Liu, Yanqiao Zhang","doi":"10.1158/2326-6066.CIR-25-1617","DOIUrl":"10.1158/2326-6066.CIR-25-1617","url":null,"abstract":"<p><p>In esophageal squamous cell carcinoma (ESCC), chemoradiotherapy potentiates the effects of immune checkpoint inhibitors by activating the tumor-intrinsic innate immune response. However, ESCC cells frequently suppress this activation, which contributes to the high rates of immunotherapy resistance (70%-80%) observed clinically. Thus, identifying intracellular suppressors of this innate immune response remains an unmet critical need. Herein, through multiomics analyses, we identify the chromatin assembly factor CHAF1A as a suppressor of the tumor-intrinsic innate immune response in ESCC. We found that CHAF1A was overexpressed in ESCC and negatively correlated with type I interferon production and CD8+ T-cell infiltration. Mechanistically, CHAF1A maintained heterochromatin silencing mediated by H3K9me3, thereby repressing endogenous retroviruses. This suppression prevented the accumulation of double-stranded RNA and the subsequent activation of the MAVS-IRF3 signaling pathway. Concurrently, CHAF1A preserved genomic stability, limiting the release of double-stranded DNA and activation of the cGAS-STING pathway. Loss of CHAF1A potentiated the response to immunotherapy through the coordinated activation of these dual pathways. We then performed a small-molecule compound screen and identified a CHAF1A inhibitor, baimaside, which enhanced the effect of anti-PD-1 therapy to augment antitumor immunity. Collectively, these data indicate that CHAF1A represents a potential therapeutic target for sensitizing ESCC to immunotherapy and provide a potential combination strategy for reversing immunotherapy resistance.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1635-1652"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148469206","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":"BET Inhibition Synergizes with RLR Signaling to Enhance Tumor Immunogenicity and T-cell Recognition.","authors":"Lucas Baldran-Groves, Rok Žiberna, Marc-Antoine Gerault, Mireia Cruz De Los Santos, Adela Kiessling, Sylvya Pasca, Nooshin Khoshdoozmasouleh, Andreas Post, Andreas Lundqvist, Stina Wickström, Rolf Kiessling, Jeroen Melief","doi":"10.1158/2326-6066.CIR-25-0777","DOIUrl":"10.1158/2326-6066.CIR-25-0777","url":null,"abstract":"<p><p>Intratumoral signaling via the cytosolic double-stranded RNA (dsRNA) receptors RIG-I and MDA-5 enhances antitumor immunity and can overcome resistance to cancer immunotherapy. Although bromodomain extraterminal (BET) proteins are established epigenetic drivers of immune escape mechanisms, their role in regulating RIG-I-like receptor (RLR) signaling remains undefined. Therefore, we investigated the role of BET proteins in modulating innate antiviral responses to cytosolic dsRNA in tumor cells and how BET inhibition combined with dsRNA stimulation influences tumor immunogenicity and recognition by T cells. To address this, human tumor cell lines were treated with the BET inhibitor (BETi) JQ1 and transfected with the synthetic viral dsRNA analog poly(I:C) (pIC) to stimulate innate antiviral signaling. We found that BET inhibition synergistically amplifies dsRNA-induced immunogenicity, as indicated by enhanced cytokine and chemokine production, JAK-STAT signaling, antigen presentation, and immunogenic cell death. Combined treatment of melanoma cells with JQ1 and pIC resulted in a marked, synergistic enhancement of recognition by autologous tumor-specific CD8+ tumor-infiltrating lymphocytes and maturation of dendritic cells. Furthermore, an antiviral gene signature induced by pIC and enhanced by JQ1 correlated with immune infiltration and improved survival in larger patient cohorts across different types of cancer. Overall, our findings demonstrate that targeting BET proteins in tumor cells strongly potentiates dsRNA-induced antiviral responses and suggest that combining BETis with RLR agonists offers a pharmacologic strategy to enhance antitumor T-cell responses and improve the clinical efficacy of cancer immunotherapies.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1670-1684"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635740/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148419095","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":"The Gut Microbiome Drives Endogenous T-cell Activation Following CAR T-cell Therapy.","authors":"Kejia Hu, Lele Jin, Zidan Feng, Qinru Yu, Xiaohui Si, Lijuan Ding, Yingli Han, Meng Zhu, Ce Shi, Xiangjun Zeng, Kaiting Wang, Jieping Wei, Yuqi Lv, Delin Kong, Lulu Qin, Li Yu, Lixin Wang, Mingming Zhang, Pengxu Qian, Yongxian Hu, Dongrui Wang, He Huang","doi":"10.1158/2326-6066.CIR-25-1230","DOIUrl":"10.1158/2326-6066.CIR-25-1230","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy has become a promising clinical approach against hematologic malignancies, but patients receiving CAR T-cell therapy still present inconsistent clinical outcomes and are complicated by incomplete tumor eradication. The gut microbiome has shown a strong correlation with the therapeutic outcomes of CAR T-cell therapy. However, the underlying mechanism of how gut microbiota affect CAR T-cell therapeutic potency remains undetermined. In this study, we established a syngeneic CD19+ murine lymphoma model that allows for the evaluation of both endogenous immune cells and gut microbiota following CD19-CD28ζ CAR T-cell therapy. Using single-cell transcriptomic analyses, we report that CAR T-cell infusion led to the activation of peripheral and gut-infiltrating endogenous CD8+ T cells toward an effector-like phenotype. In parallel, 16S RNA sequencing revealed substantial alterations in gut microbiota after infusion. The composition of gut bacteria was associated with the activation status of endogenous CD8+ T cells and responsiveness to CAR T-cell therapy. More specifically, we identified gut bacteria strains Turicibacter and Parvibacter as critical determinants of effective CAR T-cell treatment. Supplementation with these species of gut bacteria during CAR T-cell therapy led to superior antitumor efficacy. Furthermore, both strains facilitated CAR T-cell therapy-induced activation of endogenous CD8+ T cells, enhancing their capability to express activation-associated surface markers as well as tumor lysis potency. In summary, our results demonstrate that the gut microbiome plays an essential role in endogenous immune activation after CAR T-cell therapy and provide specific targets for therapeutic interventions.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1570-1586"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148560715","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":"Meditope-Enabled Chimeric Antigen Receptors Facilitate Plug-and-Play Control of T Cells.","authors":"Cheng-Fu Kuo, Zhen Tong, Yi-Chiu Kuo, Miso Park, Jeremy King, Kevin Ly, Bea Parcutela, Lawrence A Stern, Zhiqiang Wang, Jonathan C Hibbard, Brenda Aguilar, Renate Starr, Wen-Chung Chang, Julie R Ostberg, Daniel Rossi, Mary C Clark, Darya Alizadeh, Stephen J Forman, John C Williams, Christine E Brown","doi":"10.1158/2326-6066.CIR-25-1285","DOIUrl":"10.1158/2326-6066.CIR-25-1285","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cells have transformed cancer treatment, yet challenges for achieving broader clinical success remain, including overcoming tumor antigen heterogeneity and limited T-cell fitness. To address these challenges and enhance CAR T-cell functionality, we leveraged meditope technology, a lock-and-key platform where fragment antigen-binding (Fab) regions of antibodies are modified to bind a small cyclic peptide termed meditope peptide (meP). We developed a panel of meditope-enabled Fab-based CARs (meCAR), which showed selective binding to the meP and comparable activity with traditional single-chain variable fragment-based CARs. Focusing on HER2-targeted meCARs for evaluating platform utility, we exploited the modularity of the meditope platform to detect meCAR T cells using meP-fused fluorescent agents, promote meCAR T-cell expansion via meP-fused IL15 cytokine, and broaden tumor antigen targeting through meP-fused antibodies to address tumor heterogeneity. These findings establish the meditope technology as a versatile strategy to augment CAR T-cell functionality and overcome key limitations of current CAR-based therapies. See related Spotlight, p. 1536.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1553-1569"},"PeriodicalIF":7.9,"publicationDate":"2026-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13635739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700757","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":"Immunometabolic Profiling of T Cells and Innate Lymphoid Cells Uncovers Therapeutic Targets to Enhance Immunotherapy in Head and Neck Cancer.","authors":"Sujeetha A Rajakumar, Namya Nanda, Chloe Kim, Dustin Dikeman, Tanguy Y Seiwert, Zubair Khan, Sewon Kang, Carole Fakhry, Martin P Alphonse","doi":"10.1158/2326-6066.CIR-26-0245","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0245","url":null,"abstract":"<p><p>Immunometabolic reprogramming governs antitumor immunity, yet its role in checkpoint blockade responses remains poorly defined. Using functional-metabolic flow cytometry, we characterized tumor-infiltrating mucosal-associated invariant T (MAIT) cells, CD8 T cells, and innate lymphoid cells (ILCs) from head and neck squamous cell carcinoma (HNSCC) patients receiving neoadjuvant anti-programmed cell death protein 1 (PD-1) monotherapy or combined anti-PD-1/anti-interleukin-8 (IL-8) therapy. We identified CD39-negative OX40 MAIT and CD8 tumor-infiltrating lymphocytes (TILs) as metabolically fit, less-exhausted populations. In contrast, OX40- cells exhibited elevated glucose-6-phosphate dehydrogenase (G6PD) expression, identifying the pentose phosphate pathway as a targetable metabolic vulnerability. Ex vivo transcriptomic analysis of CD8 TILs from untreated patients revealed CD39-stratified responses to anti-PD-1/polydatin (G6PD inhibitor) combination treatment: CD39-negative cells amplified effector programs; CD39-medium cells shifted toward lipid catabolism; and CD39-high exhausted cells showed downregulation of STAT3 and mTOR-pathway genes only under combination treatment, consistent with a shift in metabolic regulation. Secretome profiling confirmed the functional translation of this reprogramming, with combination treatment significantly increasing soluble CD27 secretion in CD39-high TILs-indicating enhanced activation in terminally exhausted populations. ILC profiling identified immunosuppressive CD294-high ILC2s, marked by elevated C-C-motif chemokine receptor 8 (CCR8) and carnitine palmitoyltransferase 1A (CPT1A) protein expression, as a potential barrier to checkpoint blockade efficacy. Conversely, CD39-negative ILC3s emerged as metabolically active populations amenable to therapeutic reprogramming. These findings establish immunometabolic profiling as a framework for guiding precision checkpoint blockade combinations in HNSCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073620","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}