Lipid signalling enforces T(reg) cell functional specialization in tumours

Regulatory T (T(reg)) cells are essential for immune tolerance1 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.