All-trans retinoic acid suppresses CD8+ T-cell terminal exhaustion and potentiates anti-PD-1 therapy in glioblastoma

Terminal exhaustion of CD8⁺ T cells limits the efficacy of immune checkpoint blockade (ICB), particularly in glioblastoma, which is characterized by an immunosuppressive tumor microenvironment. Therefore, a better understanding of the regulators of terminal exhaustion could overcome intrinsic resistance to ICB and improve the efficacy of immunotherapy. In this study, we report that all-trans retinoic acid (ATRA) suppresses CD8⁺ T-cell terminal exhaustion. The administration of ATRA during CD8⁺ T-cell activation in vitro conferred resistance to terminal exhaustion and preserved effector cytokine production and effector function. Mechanistically, ATRA selectively induced the expression of the long isoform of T-cell factor 1 (TCF-1 βBD ) through activation of the canonical WNT/β-catenin pathway. In a mouse glioma model, adoptively transferred ATRA-conditioned CD8⁺ T cells exhibited increased TCF-1 βBD and β-catenin expression and resistance to exhaustion, which led to superior tumor-infiltrating CD8 + T-cell polyfunctionality and enhanced glioma suppression. Importantly, oral administration of ATRA also suppressed terminal exhaustion of tumor-infiltrating CD8 + T cells and synergized with anti-PD-1 therapy, overcoming resistance to immune checkpoint blockade (ICB) in two mouse models of glioma. Combined ATRA and anti-PD-1 treatment also displayed synergistic therapeutic potential by significantly reducing recurrence in a mouse model of glioma that had undergone surgical resection. Single-cell transcriptomic analysis of glioblastoma patients receiving anti-PD-1 therapy revealed that CD8⁺ T cells from responders were enriched in genes that respond to retinoic acid and WNT-associated genes, which correlated with improved survival. These findings establish ATRA as a modulator of CD8⁺ T-cell exhaustion through the induction of WNT/β-catenin-dependent TCF-1 βBD expression, suggesting that ATRA has therapeutic potential for overcoming resistance to ICB in glioma.