ACSL4-programmed sphingomyelin metabolism rejuvenates tumor-infiltrating T-cells to enhance efficacy of anti-PD-1 immunotherapy (ATAC-seq)
Energy metabolism is central for the control of T-cell fate and functional status. Despite the clinical success of PD-1-targeted therapy, the metabolic mechanisms underlying the T cell unresponsiveness to immunotherapy for the majority of patients with cancer still remain unexplored. Here we dissected the metabolic discrepancy of tumor-infiltrating lymphocytes (TILs) in melanoma patient cohorts between responders and non-responders. Intriguingly, we observed that while TILs in responders exhibited improved metabolic fitness after ICI treatment, those in non-responders demonstrated crippled metabolic reinvigoration, particularly for the fatty acid metabolism. This scenario was further evidenced in mice showing that T cell-specific depletion of Acyl-CoA synthetase long-chain family member 4 (ACSL4), a key enzyme important for the initiation of fatty acid metabolism, completely abrogated the ICI-mediated tumor regression and survival benefit in mice bearing established tumors, indicating the importance of fatty acid metabolism in antitumor responses. Mechanistically, ACSL4 deficiency changed the chromatin states of NFAT and TOX and thus defined a switch from activation to exhaustion in TILs. Metabolomics analysis further revealed a primary perturbation of sphingomyelin metabolism after ACSL4 deficiency. In contrast, supplementation of sphingomyelin metabolites significantly reverted ACSL4 deficiency-induced TIL dysfunction through attenuation of the chromatin accessibility of TOX and synergize with anti-PD-1 treatment. Overall, our findings demonstrated that navigating metabolic pathways in TILs towards improved sphingomyelin metabolism might be crucial for the activation of immune responses to immunotherapy in cancer patients.