All -trans retinoic acid suppresses CD8+ T cell terminal exhaustion which enhances anti–PD-1 efficacy against glioblastoma

Moreover, in a mouse glioma model, ATRA administration promoted CD8⁺ T cell exhaustion resistance, which led to superior tumor-infiltrating CD8+ T cell polyfunctionality and enhanced anti-glioma responses. Oral administration of ATRA also synergized with anti–PD-1 therapy, overcoming resistance in two mouse models of glioma. Single-cell transcriptomic analysis of anti–PD-1–treated glioblastoma patients revealed that CD8⁺ T cells from responders were enriched for retinoic acid–responsive and WNT-associated gene signatures, which correlated with improved survival.

These findings establish ATRA as a suppressor of CD8⁺ T cell exhaustion by inducing WNT/β-catenin–dependent TCF-1p45 expression. This pathway offers therapeutic potential to overcome resistance to immune checkpoint blockade in glioma, and it may also offer strategies to improve cell therapies, such as adoptive cell transfer.