Abstract

Abstract The survival and functional performance of NK cells is a metabolically demanding process. However, there is largely unknown how inappropriate metabolic reprogramming underlies disease microenvironments leads to NK dysfunction. Here, through analysis of human liver cancer samples (n=102) and benign liver samples (n=22), we found tumor infiltrative NK (TINK) cells present small and fragmented mitochondria in the cytoplasm, while normal liver NK and peripheral NK cells have big and tubular mitochondria. We also observed hypoxic tumor microenvironment is the main factor to induce NK cell excessive mitochondrial fission into fragmentation and that dependent on increasing Drp1 activity. Consequently, the fragmentation causes the metabolic disturbance and losing of TINK cells and that predicts poor survival in liver cancer patients. Revising mitochondrial morphology by targeting Drp1 improves mitochondrial metabolism and anti-tumor capacity of NK cells. Thus, disease-related mitochondrial restructuring drives NK cell exhaust and that is manipulated to the benefit of temper or enhance immunity.

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