Lipid signalling enforces T _reg cell functional specialization in tumours

Abstract

Regulatory T (T _reg) cells are essential for immune tolerance 1 but also drive immunosuppression in the tumour microenvironment (TME) 2. Therapeutic targeting of T _reg cells in cancer requires the identification of context-specific mechanisms for T _reg cell function. Here we demonstrate that inhibition of sterol regulatory element-binding protein (SREBP)-dependent lipid synthesis and metabolic signalling in T _reg cells unleashes effective antitumour immune responses without autoimmune toxicity. SREBP activity is upregulated in intratumoural T _reg cells, and T _reg cell-specific deletion of SCAP, an obligatory factor for SREBP activity, inhibits tumour growth and boosts anti-PD-1 immunotherapy, associated with uncontrolled IFN-γ production and impaired function of intratumoural T _reg cells. Mechanistically, SCAP/SREBP signalling coordinates lipid synthetic programs and inhibitory receptor signalling in T _reg cells. First, de novo fatty acid synthesis mediated by fatty acid synthase (FASN) contributes to functional maturation of T _reg cells, and loss of FASN in T _reg cells inhibits tumour growth. Second, T _reg cells show enhanced Pdcd1 expression in tumours in a process dependent on SREBP activity that further signals to mevalonate metabolism-driven protein geranylgeranylation, and blocking PD-1 or SREBP signaling results in dysregulated PI3K activation in intratumoural T _reg cells. Our findings establish that metabolic reprogramming enforces T _reg cell functional specialization in tumours, pointing to new avenues to target T _reg cells for cancer therapy.