Oncoimmunology最新文献

{"title":"Pooled analysis of 2 clinical trials of first-line chemoimmunotherapy for metastatic microsatellite stable colorectal cancer MEDITREME and METIMMOX studies.","authors":"Caroline Truntzer, Marion Thibaudin, Paula Anna Bousquet, Morgane Peroz, Valentin Derangère, Alis Ilie, David Rageot, Kjersti Flatmark, Anne Hansen Ree, Sebastian Meltzer, François Ghiringhelli","doi":"10.1080/2162402X.2026.2671491","DOIUrl":"10.1080/2162402X.2026.2671491","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer with microsatellite stable (MSS) status is intrinsically resistant to immune checkpoint inhibitor monotherapy targeting PD-1 or PD-L1. However, emerging evidence suggests that chemotherapies may overcome this resistance when combined with immunotherapy.</p><p><strong>Methods: </strong>We conducted a pooled analysis of individual patient data from two phase II trials evaluating oxaliplatin-based chemotherapy combined with checkpoint inhibitors as first-line treatment for MSS metastatic colorectal cancer. The MEDITREME trial is a single-arm study assessing durvalumab and tremelimumab with oxaliplatin-based chemotherapy, while the METIMMOX trial is a randomized study comparing standard oxaliplatin-based chemotherapy with an alternating regimen of oxaliplatin-based chemotherapy and nivolumab. We compared overall survival (OS), progression-free survival (PFS), and response rates between patients treated with chemotherapy alone <i>versus</i> chemoimmunotherapy, and evaluated the association between these outcomes and transcriptomic and immunoscore data.</p><p><strong>Results: </strong>A total of 130 patients were included: 38 who received chemotherapy alone and 92 chemoimmunotherapy. The median OS was significantly improved in the chemoimmunotherapy group compared with chemotherapy alone (not reached <i>vs</i>. 15.3 months; HR = 0.58; 95% CI, 0.36-0.96; <i>p</i> = 0.03). The complete response rates were higher with chemoimmunotherapy (14% <i>vs</i>. 5%). No significant differences were observed in PFS. High baseline CD8⁺ T-cell infiltration was associated with improved outcomes in patients receiving chemoimmunotherapy but not in those treated with chemotherapy alone.</p><p><strong>Conclusions: </strong>This pooled analysis provides compelling evidence supporting the clinical benefit of first-line chemoimmunotherapy in a subset of patients with MSS mCRC. Baseline CD8⁺ T-cell infiltration may serve as a predictive biomarker for identifying patients most likely to benefit from this treatment approach.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2671491"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148297094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers of subclinical cholestasis predict cancer immunotherapy outcomes.","authors":"Anne-Laure Mallard de La Varende, Marine Fidelle, Guido Kroemer, Laurence Zitvogel","doi":"10.1080/2162402X.2026.2748140","DOIUrl":"10.1080/2162402X.2026.2748140","url":null,"abstract":"<p><p>In a recent paper published in Cancer Cell, we identified subclinical cholestasis as an accessible imprint of gut dysbiosis predicting resistance to immune checkpoint blockade. Our work connects <i>γ</i>-glutamyl transferase, bile-acid remodeling, and MAdCAM-1 loss to compromised antitumor immunity, opening avenues for novel biomarker-guided microbiota interventions.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2748140"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197394","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glioblastoma immune landscape remodeling following treatment with CD70-targeted CAR-T cells.","authors":"Alexandros Kourtesakis, Dennis Alexander Agardy, Clara Tejido Dierssen, Ling Hai, Dirk Carsten Frieder Hoffmann, Normann Mussnig, Ralph Sinn, Manuel Fischer, Andy Schacht, Michael Breckwoldt, Lukas Bunse, Tim Sauer, Michael Platten, Wolfgang Wick, Tobias Kessler","doi":"10.1080/2162402X.2026.2745295","DOIUrl":"10.1080/2162402X.2026.2745295","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cell therapy has shown limited efficacy in glioblastoma (GB), largely because of the immunosuppressive tumor microenvironment (TME). We have previously demonstrated that the ligand-based mCD70-directed construct mCAR27 specifically eliminates CD70⁺ GB cells <i>in vitro</i>, and induces durable tumor remission with prolonged survival in a syngeneic model of orthotopic GB. Despite the therapeutic promise of CD70 as a GB CAR-T cell target, the impact of CD70-directed CAR-T cells on the brain tumor immune landscape after target interception remains unexplored. Here, we independently confirmed a tumorigenic role for CD70 in murine GB by performing bulk RNA sequencing and <i>in vivo</i> experiments. Next, we applied single-cell RNA sequencing (scRNAseq) to decipher the transcriptome of GB-infiltrating immune cells in immunocompetent mice bearing CD70⁺ GB after intratumoral mCAR27 therapy. CAR-T cell treatment expanded adoptively transferred cells and was associated with increased endogenous Cd8⁺ T-cell infiltration, alongside a reduction in immunosuppressive populations, including T_regs and anti-inflammatory M2-like macrophages, but also subsets of dendritic and natural-killer cells. CD70 expression was detected on multiple GB-infiltrating immune subsets, notably T_regs and M2-like macrophages. Transcriptionally, mCAR27-mediated GB remission led to a coordinated downregulation of type-I interferon-stimulated genes and immunosuppressive mediators such as <i>Arg1</i>, <i>Tgfbi</i>, <i>Cd274</i>, <i>Pdcd1lg2</i> and <i>Lag3</i>, coupled with upregulation of genes involved in inflammatory resolution, findings consistent with attenuation of GB-derived inflammatory stress and immunosuppression. Collectively, we showcase that CD70-directed CAR-T cell therapy remodels the post-treatment immune landscape towards resolution of inflammation and reduced immunosuppression, supporting sustained immune surveillance.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2745295"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13682394/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149220700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estradiol-associated extracellular signaling in the human breast <i>in vivo</i> identifies mast cells as tumor-supportive stromal mediators.","authors":"Annelie Abrahamsson, Xingyue Wang, Wen Zhong, Charlotta Dabrosin","doi":"10.1080/2162402X.2026.2746847","DOIUrl":"10.1080/2162402X.2026.2746847","url":null,"abstract":"<p><p>Sex steroid exposure is a major risk factor for breast cancer initiation and progression through incompletely understood mechanisms. Novel therapeutics for prevention and treatment of estrogen-dependent breast cancer are needed. Cell-cell interactions within the microenvironment contribute to breast cancer progression through extracellular signaling. Here, extracellular proteins were sampled directly from live normal human breast tissue and breast cancers using microdialysis, and 1,101 proteins were quantified. Mechanistic studies were performed in cultured intact normal human breast tissue and mast cells. Findings were validated <i>in vivo</i> using ER⁺ breast cancer models in immunocompetent and immunocompromised mice and in a zebrafish xenograft model. We identified a breast tissue-specific extracellular protein signature comprising 150 proteins associated with local estradiol (E2) levels, of which several were linked to mast cell biology, including stem cell factor (SCF). Human ER⁺ breast tumors exhibited increased extracellular SCF levels and higher mast cell density, which was associated with poorer overall survival. In normal human breast tissue, E2 increased mast cell abundance and activity. <i>In vitro</i>, E2 rapidly activated mast cells, an effect blocked by desloratadine. In mouse breast cancer models, E2 increased and fulvestrant reduced mast cell density. In the zebrafish, mast cells promoted ER⁺ breast cancer growth, which was further enhanced by E2 and abrogated by desloratadine. Overall, our findings identify mast cells as estrogen-responsive stromal mediators and support targeting mast cell-dependent pathways as a potential strategy for the prevention and treatment of estrogen-dependent breast cancer.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2746847"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13671425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149185336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Alistipes</i> and <i>Eggerthella</i> shape the response to oncolytic adenovirus therapy in mice and humans through short-chain fatty acid metabolism.","authors":"Mirte van der Heijden, James Hugo Armstrong Clubb, Pande Putu Erawijantari, Aki Ronkainen, Victor Arias, Elise Jirovec, Tatiana Kudling, Santeri Artturi Pakola, Nea Ojala, Lyna Haybout, Saru Basnet, Susanna Grönberg-Vähä-Koskela, Sini Karoliina Raatikainen, Otto Hemminki, Anna Kanerva, Dafne Carolina Alves Quixabeira, Victor Cervera-Carrascon, João Manuel Dos Santos, Leo Lahti, Akseli Hemminki","doi":"10.1080/2162402X.2026.2656514","DOIUrl":"10.1080/2162402X.2026.2656514","url":null,"abstract":"<p><p>Accumulating evidence implicates the microbiome as an important determinant of clinical outcomes in cancer therapies; however, the role of the microbiome in oncolytic virus therapy remains largely unexplored. We investigated the gut microbiome of cancer patients following treatment with the oncolytic adenovirus igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2; TILT-123). Baseline fecal samples from phase I clinical trials (NCT04695327 and NCT05271318) were analyzed using shotgun metagenomic sequencing and compared to treatment outcomes. A higher relative abundance of <i>Alistipes</i> was observed in patients with treatment benefit, while elevated <i>Eggerthella</i> was observed with reduced benefit. These associations were validated in a preclinical mouse model where administration of <i>Alistipes shahii</i> improved the efficacy of adenovirus therapy. In addition, enrichment analysis in patient samples showed a positive correlation between higher relative abundance of <i>Alistipes</i> and elevated short-chain fatty acids in both feces and serum, which in turn revealed higher circulating neutrophil counts. Finally, in a case study, we observed that adenovirus treatment resulted in increased <i>Alistipes</i> relative abundance and reduced <i>Eggerthella</i> relative abundance, indicating that adenovirus therapy may beneficially modulate the microbiome. Overall, our findings reveal a novel association between <i>Alistipes</i>, <i>Eggerthella</i>, and the therapeutic response to oncolytic adenovirus therapy, highlighting their potential as biomarkers or targets for microbiome-based interventions such as pre-, pro-, or postbiotics.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2656514"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374768/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex-based considerations in the choice for a TLR9 or TLR7/8 agonist to arm the sentinel lymph node in early-stage melanoma.","authors":"Jessica C L Notohardjo, Elisa C Toffoli, Tara Muijlwijk, Mari F C M van den Hout, Vinitha Kandiah, Mariette Labots, Rieneke van de Ven, Alfons J M van den Eertwegh, Tanja D de Gruijl","doi":"10.1080/2162402X.2026.2662708","DOIUrl":"10.1080/2162402X.2026.2662708","url":null,"abstract":"<p><p>Intradermal delivery of the Toll-like receptor (TLR)-9 agonist agatolimod/CPG7909, prior to sentinel lymph node (SLN) biopsy was previously shown to induce locoregional and systemic immunity, reduce tumor-involved SLN rates, and improve recurrence-free survival in patients with early-stage melanoma. Remarkably, men exhibited superior dendritic cell (DC) maturation. Here, we report on further sex-based differences in the immune response after intradermal administration of CPG7909, which included higher CD80/CD83 expression levels in conventional (c) DC subsets in men's as compared to women's SLN, as well as higher <i>ex-vivo</i> release levels of IL-1β, TNF, and IL-6 (all contributors to cDC activation) and Th1/Th2 cytokines. In an effort to identify a more effective DC-activating therapy for women, we compared the in-vitro effects of CPG7909 with those of the TLR7/8 agonist resiquimod/R848 on SLN single cells from female patients. R848 induced superior cDC subset activation and TNF, IL-6, IL-10, IL-12, IFNγ, and CXCL10 release. Correlation analyses suggested that IFNα, TNF, and IL-6 were key for CPG7909-induced LNR-cDC activation, whereas R848's effect appeared more cytokine-independent. We conclude that combining locally delivered CPG7909 and R848 in early-stage melanoma will ensure full-range DC subset activation and robust pro-inflammatory T-cell responses in melanoma SLN, independent of sex.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2662708"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13166185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147844759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Local delivery of SBRT and IL-12 to murine PDAC tumors modulates hematopoiesis.","authors":"Tara G Vrooman, Emily R Quarato, Gary Hannon, Noah A Salama, Maggie L Lesch, Angela L Hughson, Vedika S Chandak, Nataliia Vdovichenko, Zhiming Jin, Ronald Lakony, Jian Ye, Sarah L Eckl, Sidney Lesser, Edith M Lord, David C Linehan, Haoming Qiu, Nadia Luheshi, Jim Eyles, Laura M Calvi, Scott A Gerber","doi":"10.1080/2162402X.2026.2682058","DOIUrl":"10.1080/2162402X.2026.2682058","url":null,"abstract":"<p><p>Standard of care radiotherapy and chemotherapy have shown limited efficacy in pancreatic ductal adenocarcinoma (PDAC). Immunotherapy has emerged as a promising treatment but has been hindered by systemic toxicities. A shift from systemic to localized delivery has reduced adverse effects and improved response rates in various cancers. However, the impact of tumor-targeted therapies on distant tissues, such as the bone marrow, remains underexplored. In a murine model of PDAC, we treated tumors with targeted stereotactic body radiation therapy (SBRT) and intratumoral interleukin-12 mRNA (IL-12). We evaluated tumor, blood, and bone marrow cells for therapy-induced changes over a period of 13 d to 13 months. Our results showed that while SBRT/IL-12 locally eradicated primary tumors, it also induced significant effects in the bone marrow. Early effects included acute lymphopenia in the blood and an immunostimulatory response in the bone marrow, leading to increased hematopoiesis. Long-term effects involved a reduction in hematopoietic stem cells (HSCs) and a shift towards a myeloid lineage, suggesting potential premature aging of the HSC population. These findings highlight the profound impact of localized SBRT/IL-12 therapy on distal bone marrow, emphasizing the need for further investigation into the long-term immunological consequences of localized cancer treatments.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2682058"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13245092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148164827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sex determines the natural killer cell-mediated immunity against pancreatic cancer.","authors":"Elise Arlt, Nadine Bley, Alexander Rausch, Sandra Hauser, Jens Pietzsch, Danny Misiak, Thomas Liehr, Stefanie Kankel, Theresa Dautz, Luisa Dreher, Xiángméng Kǒng, Heike Kielstein, Ivonne Bazwinsky-Wutschke","doi":"10.1080/2162402X.2026.2645298","DOIUrl":"10.1080/2162402X.2026.2645298","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) ranks among the most aggressive malignancies and exhibits a higher prevalence and poorer prognosis in male patients. While both the importance of natural killer (NK) cells in anti-tumor immunity and sex differences in NK cell function are well established, the interplay between biological sex and NK cell-mediated responses in PDAC has not been systematically addressed. Here, we provide novel insights revealing that both the intrinsic cytotoxic capacity of NK cells and the tumor microenvironment differ between sexes and jointly modulate anti-tumor immunity in PDAC. Using <i>in vitro</i> assays with primary NK cells from male and female mice, we found that female-derived NK cells exhibit consistently superior cytotoxic activity and immune activation. Importantly, these findings were reflected and even amplified <i>in vivo</i>. In a syngeneic allograft PDAC model, female mice displayed enhanced NK cell function, and female tumors exhibited distinct structural characteristics supporting stronger NK cell activity. Notably, this occurred despite the use of the same cell line in both sexes, indicating that host sex significantly shapes the composition and architecture of the tumor microenvironment. Our results provide new evidence that sex differences in NK cell-mediated immunity, within the broader immune and stromal landscape, may differentially impact tumor control in male and female PDAC hosts. This study therefore underscores the importance of considering sex as a biological variable in the preclinical evaluation of pancreatic cancer therapies.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2645298"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13014558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147505390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Telomere damage enhances immunogenicity of neuroblastoma and accelerates response to anti-PD-L1 treatment.","authors":"Stefanie Höppner, Lisa Werr, Beata Szilagyi, Christoph Bartenhagen, Anna-Maria Hellmann, Carolina Rosswog, Emma Linden, Gerrit Primke, Yvonne Kahlert, Nadliv Ibruli, Nadine Hemstedt, Witali Lorenz, Johannes Brägelmann, Michael Hölzel, Matthias Fischer","doi":"10.1080/2162402X.2026.2653918","DOIUrl":"10.1080/2162402X.2026.2653918","url":null,"abstract":"<p><p>Telomerase is active in the majority of high-risk neuroblastomas, a pediatric tumor associated with poor patient outcomes. In other cancer types, resistance to immune checkpoint blockade was overcome by induction of telomere dysfunction using the telomerase substrate precursor 6-thio-2'-deoxyguanosine (6-thio-dG). Here, we explored whether induction of telomere dysfunction improves the anti-tumor efficacy of immune checkpoint inhibition in neuroblastoma. 6-thio-dG treatment induced the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and programmed cell death ligand-1 (PD-L1) expression in murine neuroblastoma cells <i>in vitro</i>. In a <i>MYCN;ALK</i>^{<i>F1174L</i>}-driven transgenic neuroblastoma mouse model, 6-thio-dG treatment delayed tumor growth and prolonged survival. Treatment with anti-PD-L1 also led to growth delay and improved survival, which occurred; however, only after an initial lag phase. Combination with anti-PD-L1 improved the anti-tumor effects of 6-thio-dG and overcame the initial lag phase of anti-PD-L1 treatment. Mechanistically, 6-thio-dG combined with anti-PD-L1 treatment induced cGAS and PD-L1 expression and promoted immune cell infiltration in the tumors. Our findings suggest that 6-thio-dG treatment activates the cGAS-STING pathway in neuroblastoma and that induction of telomere dysfunction in combination with immune checkpoint blockade boosts intratumoral immune cell infiltration and improves survival in a high-risk neuroblastoma mouse model.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2653918"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13064559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147634016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myeloid-derived MIF is a central regulator of MDSC-driven T-cell dysfunction in head and neck squamous cell carcinoma.","authors":"Suvekshya Shrestha, Felipe Lamenza, Natalie Kazmierowicz, Kishan Kumar Nyati, Sushmitha Jagadeesha, Ravi Ramalingam, Reegan Kehres, Puja Upadhaya, Arham Siddiqui, Shaheer Masood, Massar Yade, Sonali Dasari, Steve Oghumu","doi":"10.1080/2162402X.2026.2719293","DOIUrl":"https://doi.org/10.1080/2162402X.2026.2719293","url":null,"abstract":"<p><strong>Background: </strong>Head and neck squamous cell carcinoma (HNSCC) exhibits a profoundly immunosuppressive tumor microenvironment (TME) enriched for myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and dysfunctional CD8⁺ T cells, limiting therapeutic benefit from immune checkpoint blockade. Macrophage migration inhibitory factor (MIF) is elevated in HNSCC and linked to poor outcomes, yet the cellular source and functional role of tumor-promoting MIF in shaping antitumor immunity remain unclear.</p><p><strong>Methods: </strong>We used a myeloid-specific MIF knockout mouse (mMIF KO) in an orthotopic MOC2 HNSCC model and evaluated immune function using <i>ex vivo</i> co-cultures of tumor-derived MDSCs with naïve T cells under Treg-skewing, basal, or Th1-polarizing conditions.</p><p><strong>Results: </strong>Myeloid-restricted MIF deletion significantly reduced tumor growth and increased CD8⁺ T cell infiltration, accompanied by reduced CTLA4, TIGIT, and TIM3 expression, with elevated PD1 consistent with antigen-engaged effector activation. High-dimensional immune profiling revealed expansion of cytotoxic CD8⁺ T cell states (GranzymeB^hi/Perforin^hi) and contraction of IL10-producing CD4⁺ regulatory (Tr1-like) populations, findings corroborated by decreased intratumoral CD4⁺FoxP3⁺Tregs. Within the myeloid compartment, MIF deletion selectively depleted polymorphonuclear MDSCs (PMN-MDSCs), including CSF1R^hi and PD-L1^hi subsets. Functionally, tumor-derived MDSCs lacking MIF showed impaired capacity to induce Tregs and to promote CD8⁺ T cell exhaustion in <i>ex vivo</i> co-cultures, effects partially overcome by TGFβ/Th1-polarizing signals.</p><p><strong>Conclusions: </strong>These findings identify myeloid-derived MIF as a central regulator of the MDSC-Treg-CD8⁺ axis in HNSCC and support myeloid-targeted MIF inhibition as a strategy to reprogram the TME and enhance responses to immune checkpoint blockade.</p>","PeriodicalId":48714,"journal":{"name":"Oncoimmunology","volume":"15 1","pages":"2719293"},"PeriodicalIF":6.2,"publicationDate":"2026-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13488472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148799965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}