CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors

Depleting regulatory T cells (T(reg) cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T(reg) cells is direly needed for cancer immunotherapy. We found CD36 was selectively up-regulated in intrautumoral T(reg) cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via PPAR-β signaling, programming T(reg) cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T(reg) cells suppressed tumor growth accompanied by a decrease in intratumoral T(reg) cells and enhancement of anti-tumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive anti-tumor responses with anti-PD-1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrate survival and functions of intratumoral T(reg) cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.