Short-chain fatty acids act as metabolic and epigenetic regulators in CAR T cell therapy.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, but its efficacy in solid tumors remains constrained by poor infiltration, metabolic stress, and limited persistence. Short-chain fatty acids (SCFAs), particularly butyrate and pentanoate, offer a way to influence CAR T metabolism and chromatin state during manufacturing. Butyrate combines class I histone deacetylase inhibition with acetyl-CoA metabolism and AMP-activated protein kinase (AMPK)-associated restraint of mTORC1, whereas pentanoate can reinforce effector programs through mTOR signaling and a distinct TCA-ATP-citrate lyase carbon-routing pathway. Direct CAR T studies and clinical associations now support the biological relevance of both metabolites, although their effects depend on dose, exposure schedule, cell composition, and experimental context. Building on their complementary actions, we propose sequential butyrate-pentanoate conditioning, with early butyrate exposure used to support oxidative and progenitor-associated features and later pentanoate exposure used to reinforce effector function. This review develops the mechanistic basis for that strategy, defines the experiments needed to distinguish cooperation from antagonism, and considers its manufacturing and translational implications.