Metabolic programs of T cell tissue residency empower tumour immunity

Tissue resident memory CD8⁺ T (T_RM) cells offer rapid and long-term protection at sites of reinfection¹. Tumour-infiltrating lymphocytes with characteristics of T_RM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses^2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting T_RM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8⁺ T cell populations. We found that memory CD8⁺ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where T_RM cells interface with dietary cholesterol and maintain a heightened state of activation⁴, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of T_RM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8⁺ T cell formation in the context of acute infections and enhance antitumour immunity.