Retinoic acid enhances γδ T cell cytotoxicity in nasopharyngeal carcinoma by reversing immune exhaustion

Recent studies have shown that the antitumor immunity of adaptive immune cells is regulated by Vitamin A (retinoic acid, RA). However, it remains unclear whether RA and retinoic acid receptor (RAR) signaling can modulate antitumor immunity by reversing immune exhaustion of innate-like γδ T cells in human nasopharyngeal carcinoma (NPC). Periphery blood samples from patients with NPC were prospectively collected, and phenotypic and functional analyses of γδ T cells were performed using flow cytometry. Tumor-bearing models and RAR inhibitor approaches were utilized to investigate RA/RAR-mediated regulation of T cell immunoglobulin domain and mucin domain 3 (Tim-3) and the antitumor activity of γδ T cells. Here, our findings indicate that immune exhaustion markers are highly expressed on peripheral αβ and γδ T cells in NPC patients. Serum RA levels are negatively correlated with the abundance of Tim-3 on circulating Vδ2 T cells. Mechanistic studies have demonstrated that RA/RAR signaling directly targets Vδ2 T cells, repressing Tim-3 expression, promoting NF-κB activation, and enhancing the production of antitumor-related cytokines. Notably, RA supplementation improved the efficacy of Vδ2 T cell-mediated immunotherapy in human NPC by suppressing Tim-3 expression. Collectively, these findings suggest that RA/RAR signaling plays a crucial role in reversing immune exhaustion and represents a promising target for γδ T cell antitumor immunotherapy.