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Simple Summary  In patients with advanced cancer, hypoxic stress shapes NK cells toward tumor-resistant and immunosuppressive phenotypes. Therefore, a strategy to restore NK cell function within hypoxia would be crucial for successful tumor immunotherapy. By manipulating pO 2  exposure to naïve vs. pre-activated NK cells, we found that HIF-1α-dependent metabolic reprogramming of NK cells is the key to overcoming hypoxia-mediated NK cell impairment. Exposure of pre-activated NK cells to hypoxia with 1.5% pO 2  initiated metabolic shift from oxidative phosphorylation to glycolysis and reduction of p21/p53-dependent apoptotic pathways, with concomitant upregulation of cell cycle-promoting genes and downregulation of cell cycle-arrest genes via HIF-1a/ERK/STAT3 activation. Furthermore, upregulation of NKp44 activating receptor in hypoxia-exposed pre-activated NK cells elevated cytotoxicity of K562, CEM, and A375 tumor cells, in both in-vitro and in-vivo tumor-clearance assays. Therefore, HIF-1α-mediated metabolic reprogramming of NK cells could reverse their impaired phenotype, generating functionally robust NK cells for adoptive therapy and clinical evaluation.    Abstract  NK cells are the predominant innate lymphocyte subsets specialized to kill malignant tumor cells. In patients with advanced cancer, hypoxic stress shapes NK cells toward tumor-resistant and immunosuppressive phenotypes, hence a strategy to restore NK function is critical for successful tumor immunotherapy. Here, we present evidence that pre-activation and subsequent HIF-1α-dependent metabolic shift of NK cells from oxidative phosphorylation into glycolysis are keys to overcome hypoxia-mediated impairment in NK cell survival, proliferation, and tumor cytotoxicity. Specifically, exposing NK cells to 7–9 days of normoxic culture followed by a pO 2  of 1.5% hypoxia led to a highly potent effector phenotype via HIF-1α stabilization and upregulation of its target genes,  BNIP3 ,  PDK1 ,  VEGF ,  PKM2 , and  LDHA . RNA sequencing and network analyses revealed that concomitant reduction of p21/p53 apoptotic pathways along with upregulation of cell cycle-promoting genes,  CCNE1 ,  CDC6 ,  CDC20,  and downregulation of cell cycle-arrest genes,  CDKN1A ,  GADD45A , and  MDM2  were accountable for superior expansion of NK cells via ERK/STAT3 activation. Furthermore, HIF-1α-dependent upregulation of the NKp44 receptor in hypoxia-exposed NK cells resulted in increased killing against K562, CEM, and A375 tumor targets both in-vitro and in-vivo tumor clearance assays. Therefore, hypoxic exposure on pre-activated proliferating NK cells triggered HIF-1α-dependent pathways to initiate coordinated regulation of cell cycle, apoptosis, and cytotoxicity at the global gene transcription level. Our results uncover a previously unidentified role of HIF-1α-mediated metabolic reprogramming that can reverse impaired NK effector phenotypes to generate requisite numbers of functionally robust NK cells for adoptive cellular therapy for clinical evaluation.

Hypoxia-Driven HIF-1α Activation Reprograms Pre-Activated NK Cells towards Highly Potent Effector Phenotypes via ERK/STAT3 Pathways