ArticleCancer discovery2025
Tumor-associated NK Cells Regulate Distinct CD8+ T-cell Differentiation Program in Cancer and Contribute to Resistance against Immune Checkpoint Blockers.
Article in Cancer discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- Circulating immune cell profiling in advanced cervical and endometrial cancer patients treated with PD-1 blockade, radiotherapy, and immune modulation in the PRIMMO trial.Frontiers in immunology · 2026Trial
- Advances in natural killer cell immunotherapy for hematologic malignancies.Cancer biology & therapy · 2026Review
- Unconventional functions of natural killer cells in homeostasis and disease.Journal of immunology (Baltimore, Md. : 1950) · 2026Review
- Roles of neutrophil extracellular traps in cancer immunotherapy resistance and therapeutic targeting.Biomarker research · 2026Review
- Integrated Single-Cell Profiling Reveals Dichotomous NK Cell Populations Associated with Immunosuppression in Solid Tumors.Cancer immunology research · 2026Article
- Decoding the crosstalk between ubiquitination and other post-translational modifications in cancer immunity: from mechanisms to clinical prospects.NPJ precision oncology · 2026Review
- Valrubicin-loaded immunoliposomes targeting antigens on immunosuppressive cells to circumvent resistance to cancer immunotherapy.Cell reports. Medicine · 2026Article
- UHRF2 related to sumoylation : assessment of its role in immune suppression and therapeutic potential in colorectal cancer.BMC cancer · 2026Article
- Characterization of Lymphocyte Subsets in Peripheral Blood of Patients with Colorectal Cancer.Journal of gastrointestinal cancer · 2026Article
- Winners take it all: turning cell competition into a therapeutic ally.Cell communication and signaling : CCS · 2026Review
- Innate immune signaling-driven myeloid remodeling in cancer: inflammatory amplification, immune suppression, and therapeutic targeting.Frontiers in immunology · 2026Review
- Baseline glucose-to-lymphocyte ratio predicts nivolumab outcomes in advanced non-small cell lung cancer: a multicenter retrospective study.Frontiers in immunology · 2026Article
- The Quartet of Core Oncogenic Drivers in Neuroendocrine Prostate Cancer: Multi-Omics Dataset Integration to Forge a Translational Link Between Biology and Precision Therapy.International journal of biological sciences · 2026Review
- Modulation of the PGRMC1/NLRP7/HLA-C axis by autophagy is linked to both spontaneous preterm birth and gestational choriocarcinoma.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Reprogramming natural killer cells in the tumor microenvironment: Challenges and therapeutic opportunities.Cytokine & growth factor reviews · 2025Review
- Cytotoxic NK Cells Impede Response to Checkpoint Immunotherapy in Melanoma with an Immune-Excluded Phenotype.Cancer discovery · 2025Article
- Engineered iron oxide nanoplatforms: reprogramming immunosuppressive niches for precision cancer theranostics.Molecular cancer · 2025Review
- NK cells in HPV-related tumorigenesis: mechanisms and clinical applications.Frontiers in cellular and infection microbiology · 2025Review
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Authors and funding
25 authors.
Funding
Abstract
Immune checkpoint blockers (ICB) targeting the PD-1/PD-L1 axis represent established therapies for many cancers. However, resistance occurs in most patients due to complex immune-suppressive mechanisms in the tumor microenvironment. NK cells can play effector roles in tumor control, but their impact on T-cell dysfunction and ICB efficacy remains controversial. Through genetic and antibody-mediated NK cell depletion, we found that a subset of tumor-associated NK cells plays a negative role in ICB sensitivity; they further impede CD8+ T-cell differentiation toward a CD69+ BCL2+ EOMES+ GZMB+ TIM3- GITR- phenotype. Mechanistically, the retinoic acid receptor α-dependent differentiation program in CD8+ T cells is hindered by tumor-infiltrating NK cells via competition for IFNα and IL-2. Finally, we observed that lower frequencies of NK cells correlate with better clinical responses to ICBs in patients with cancer. These findings suggest potential avenues for enhancing CD8+ T cell-centered immunotherapy by targeting regulatory NK cells. SIGNIFICANCE: Although NK cells are traditionally viewed as antitumor effectors, our study uncovers their unexpected suppressive role in CD8+ T cell-based immunotherapy. By competing for cytokines, they disrupt retinoic acid receptor α-driven CD8+ T-cell differentiation and limit ICB efficacy. Clinically, reduced NK cell presence is associated with an enhanced immunotherapy response. See related commentary by Galvez-Cancino et al., p. 1777 See related article by Pozniak et al., p. 1819.
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