Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC-I deficient solid tumors

SUMMARY Natural killer (NK) cells, a type of potent cytotoxic lymphocytes, are particularly promising for the treatment of cancers that lose or downregulate major histocompatibility complex class I (MHC-I) expression to evade T cell-mediated immunotherapy. However, the hostile and immune suppressive tumor microenvironment (TME) greatly hinders the function of tumor-infiltrating NK cells limiting the therapeutic efficacy against solid tumors. Here, we show that a fusion protein of interleukin-21 (IL-21−Fc), as a direct in vivo intervention, can safely and effectively reprogram NK cell metabolism and enhance their effector function in the TME. Our research demonstrates that combining IL-21−Fc with IL-15 superagonist (IL-15SA) or NK cell transfer leads to the eradication of MHC-I-deficient tumors and confers durable protection in syngeneic and xenograft tumor models. Mechanistically, we uncover that IL-21−Fc enhances NK cell effector function by upregulating glycolysis in a lactate dehydrogenase A (LDHA)-dependent manner. These findings not only underscore the considerable potential of IL-21−Fc as an in vivo therapeutic intervention to bolster NK cell-based immunotherapy, but also unveil an innovative strategy of metabolic reprogramming for NK cell rejuvenation within tumors. HIGHLIGHTS NK cells display functional exhaustion in MHC-I deficient solid tumors IL-21−Fc as an in vivo-applicable and safe immunotherapy reinvigorates intratumoral NK cells for enhanced effector function IL-21−Fc enhances NK cell function by elevating glycolysis in a LDHA-dependent manner Combining IL-21−Fc with low-dose IL-15SA or NK cell transfer eradicates syngeneic and xenografted solid tumors