Biphasic response of CD8 T cell to asparagine restriction maximizes its metabolic fitness and antitumoral functionality

Robust and effective T cell immune surveillance and cancer immunotherapy require properly allocating metabolic resources to sustain energetically costly processes, including growth and cytokine production. Amino acids are major cellular constituents that serve as protein building blocks, energy sources, and signaling molecules. Although T cells can synthesize all nonessential amino acids, including asparagine (Asn), activated CD8 T cells still consume considerable quantities of exogenous Asn. Unexpectedly, Asn restriction on CD8 T cells induced a biphasic response, consisting of sequential actions with opposing effects at two conceptually separated phases after activation. Asn restriction suppressed activation and cell cycle entry in the early phase by depleting the intracellular Asn pool while rapidly engaging an ATF4/NRF2-dependent stress response, conferring robust proliferation and effector function of CD8 T cells in the late phase. Mechanistically, ATF4 and NRF2 activation rendered CD8 T cells to utilize de novo biosynthesis of Asn, consuming less glucose and glutamine but producing more intracellular nucleotides for proliferation. Moreover, NRF2 activation promoted the expression of inflammatory and effector genes to enhance effector functions in CD8 T cells. Accordingly, Asn restriction or overexpression of ATF4 or NRF2 potentiated T cell-mediated antitumoral response in the metabolically restricted tumor microenvironment. Our studies revealed Asn as a critical metabolic node in directing the stress signaling to shape T cell metabolic fitness and effector functions. Asn restriction is a promising and clinically relevant strategy to enhance cancer immunotherapy.