Harnessing the PRDM1-PGC1A axis to enhance CAR T cell efficacy

Abstract

Despite its promise in treating B cell malignancies, chimeric antigen receptor (CAR) T cell therapy remains limited by resistance mechanisms that impair CAR T cell stemness, persistence, and effector function. Here, we identified PRDM1, which encodes the transcriptional repressor, BLIMP-1, as a crucial regulator of CAR T cell terminal differentiation and exhaustion. PRDM1 was highly enriched in exhausted-like tumor-infiltrating CAR T cells from lymphoma patients and in pre-infusion products from clinical non-responders. These findings link increased PRDM1 expression to CAR T cell dysfunction and poor clinical outcomes. Genetic deletion of PRDM1 significantly promoted CAR T cell proliferative capacity, memory differentiation and antitumor efficacy in both hematologic and solid tumor models. Mechanistically, PRDM1 deletion increased the activity of PGC1a;, a transcriptional coactivator central to mitochondrial biogenesis and antioxidant capacity, thereby improving mitochondrial function, oxidative stress resistance, and metabolic reserve. Depletion of PGC1a; attenuated the improved efficacy of PRDM1-deficient CAR T cells, indicating an essential role for this pathway downstream of PRDM1 loss. Pharmacologic activation of the PPAR-PGC1a; program with a clinically approved agonist, bezafibrate, enhanced CAR T cell antitumor activity without direct tumoricidal effects. Notably, transient exposure to bezafibrate during CAR T cell manufacturing was sufficient to confer durable treatment benefits. Together, our study defines a PRDM1-PGC1a; axis that controls CAR T cell differentiation, mitochondrial fitness and therapeutic response, which provides a mechanistic and translational framework for advancing CAR T cell therapy across distinct tumor contexts.