Year: 2026
Type: preprint
Abstract: 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 PGC1α, a transcriptional coactivator central to mitochondrial biogenesis and antioxidant capacity, thereby improving mitochondrial function, oxidative stress resistance, and metabolic reserve. Depletion of PGC1α 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–PGC1α 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 – PGC1Α 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.
Language: English
Topic: CAR-T cell therapy research
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7223695847