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How lipidome changes support CD8+ effector T (Teff) cell differentiation is not well understood. We found that two separate phosphoinositde (PIPn) pools, marked by different acyl chain compositions, drive important signalling events at specific stages of Teff cell differentiation. Teff cell PIPn signaling was maintained by the rapid and continuous de novo saturated PI synthesis from glucose, directly tying the nutrient environment with Teff signaling. Saturated PI synthesis was increased in CD8+ TILs, and CDIPT, which catalyses the final enzymatic step in de novo PI synthesis, was required for CD8+ TIL antitumor fitness and function. T cells with improved antitumor function following checkpoint inhibitor therapy synthesized more saturated PIPn in mouse and human melanoma.
