NF-κB inducing kinase maintains T cell metabolic fitness in antitumor immunity

Metabolic reprograming towards aerobic glycolysis is a pivotal mechanism shaping immune responses. Here we show deficiency in NF-κB-inducing kinase (NIK) impairs glycolysis induction, rendering CD8(+) effector T cells hypofunctional in tumor microenvironment. Conversely, ectopic expression of NIK promotes CD8(+) T cell metabolism and effector function, thereby profoundly enhancing antitumor immunity and improving the efficacy of T cell adoptive therapy. NIK regulates T cell metabolism via an NF-κB-independent mechanism that involves stabilization of hexokinase 2 (HK2), a rate-limiting enzyme of the glycolytic pathway. NIK prevents autophagic degradation of HK2 through controlling cellular ROS levels, which in turn involves modulation of glucose-6-phosphate dehydrogenase (G6PD), an enzyme mediating production of the antioxidant NADPH. We show that the G6PD-NADPH redox system is important for HK2 stability and metabolism in activated T cells. These findings establish NIK as a pivotal regulator of T cell metabolism and highlight a posttranslational mechanism of metabolic regulation.