Linoleic acid potentiates CD8+ T cell metabolic fitness and anti-tumour immunity

The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specificlipids can harm CD8+ T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However,the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleicacid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, andstimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances theformation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca2+) signaling, mitochondrialenergetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.