Jiannan Chen, Wenying Li, Shuai Wang, Jiayi Li, Lian‐Feng Zhao, Xudong Ao, Wenyu Wang, Zhu Li, Haipeng Rao, Shiqiang Xu, Mengru Wen, Zhigang Hu, Feiyan Pan, Lingfeng He, Lili Gu, Weijia Fang, Shengjing Xu, Junqing Liang, Peng Zhao, Haoyan Chen, Zhigang Guo
Chimeric antigen receptor (CAR)-T cell therapy has shown success in hematologic malignancies but remains limited in solid tumors due to poor persistence, migration, and tumor microenvironment-induced exhaustion. In an investigator-initiated trial in relapsed/refractory ovarian cancer, mesothelin-targeted CAR-T cells demonstrated a 75% partial response rate and good safety. To enhance efficacy, we combined CAR-T therapy with sodium valproate (VPA), a clinically approved histone deacetylase inhibitor. VPA-treated CAR-T cells (CAR-T+VPA) showed improved cytotoxicity, reduced exhaustion, and enhanced tumor infiltration. Mechanistically, VPA induced histone propionylation, particularly H3K56pr, leading to transcriptional activation of key genes. LOX promoted migration and adhesion, while GUCY1B3 enhanced metabolic fitness. CUT&Tag and RNA sequencing analyses confirmed VPA-driven epigenetic remodeling of pathways linked to T cell persistence and effector function. CAR-T+VPA cells exhibited elevated oxidative phosphorylation and glycolysis, supporting sustained activity in hostile tumor environments. In xenograft models of ovarian and triple-negative breast cancer, VPA significantly improved tumor control and survival without added toxicity. These findings support metabolic-epigenetic modulation as a strategy to improve CAR-T therapy in solid tumors.