2025/06/18 by No‐Joon Song, Juan Xie, Kyeong Joo Jung +22 · 1 voice
Medicine · Immunology and Microbiology · #Cancer Immunotherapy and Biomarkers #Immune Cell Function and Interaction #CAR-T cell therapy research
paper · doi:10.1158/2159-8290.cd-24-1232
openalex publication_date 2025/06/18 · openalex created_date 2025/06/19 · openalex updated_date 2026/07/31
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.