1α,25(OH)2D3 prevents CD19 CAR-T cell exhaustion and differentiation via VDR-dependent transcriptional reprogramming

• 1α,25(OH)2D3 significantly reduces exhaustion and enhances antitumor activity of CD19 CAR-T cells from healthy donors and DLBCL patients. • Mechanistically, 1α,25(OH)2D3 upregulates VDR expression, driving transcriptional reprogramming toward memory-like differentiation and downregulation of exhaustion genes. • In vivo xenograft models confirm that 1α,25(OH)2D3 improves CAR-T cell persistence and therapeutic efficacy. • 1α,25(OH)2D3 supplementation represents a safe, accessible strategy to improve clinical outcomes of CAR-T therapy in R/R DLBCL.