LINOLEIC ACID UNLEASHES THE ANTI-TUMOR POTENTIAL OF CD8 T CELLS BY PROMOTING METABOLIC REPROGRAMMING

T cell therapy (ACT) has achieved unprecedented clinical results in the treatment of cancer, but scarce intra-tumor infiltration, persistence and function of adoptively transferred T cells limit its efficacy, especially in solid tumors. Metabolic constraints imposed by the tumor microenvironment (TME) greatly influence the success of immune-based therapies. A common metabolic alteration in the TME is lipid accumulation, a feature often associated with defective anti-tumor responses. However, whether all lipids are detrimental to T cell functions and how they regulate different fate decisions remains poorly understood. Here, we identified Linoleic Acid (LA) as a major positive regulator of CTL activity. LA endows CTL with improved metabolic fitness and redirects them away from exhaustion and towards a memory-like phenotype with superior effector functions. Mechanistically, LA treatment fosters the formation of ER-mitochondria contacts (MERC) and mitochondrial-associated-membranes (MAMs), which in turn promotes calcium (Ca2+) signaling, mitochondrial energetics, and CTL effector functions. As a result, LA-instructed CD8+ T cells mediate superior control towards different tumor types both in vitro and in vivo following ACT on mouse models, overcoming the hustle of a highly immunosuppressive TME. Our results pave the way for a new generation of adoptive T cell-based therapies, where LA can be used during ex vivo CAR- and TCR- T cell manufacturing as a novel approach to achieve metabolic reprogramming and long-term functionality, broadening the therapeutic efficacy of ACT to a wide range of malignancies.