Modulating CAR-T cell exhaustion and fitness in acute myeloid leukemia: mechanistic metabolic and microenvironmental strategies.

Chimeric antigen receptor (CAR) T-cell therapy has achieved transformative outcomes in B-cell malignancies but remains limited in acute myeloid leukemia (AML), where antigenic heterogeneity, a suppressive myeloid-driven microenvironment, and a metabolically restrictive bone marrow niche collectively impair efficacy. In AML, CAR T-cell failure is driven not only by antigen escape but by a coordinated program of exhaustion encompassing transcriptional, epigenetic, metabolic, and functional dysfunction. The AML bone marrow niche further enforces dysfunction through suppressive immune populations, inhibitory cytokines, checkpoint signaling, metabolic competition, and impaired trafficking. This review outlines a "fitness-first" framework consolidating intrinsic and extrinsic determinants of CAR T-cell performance. Optimized manufacturing, cellular programming, and microenvironmental modulation provide a unified strategy to enhance CAR T-cell fitness and enable durable therapeutic responses in AML.