Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for Glioblastoma

Despite successful immuno-oncology therapies in other cancers, they have largely failed in glioblastoma (GBM). In this study, natural killer (NK) cells from patients with glioma show impaired oxidative phosphorylation and mitochondrial complex I activity. Multiomics profiling identified complex I subunit NDUFA9 as a critical mediator of NK cell metabolic fitness. The abundance of NDUFA9+ NK cells informed patient outcomes. Ndufa9 knockout in NK cells compromised mitochondrial function, antitumor efficacy, and the memory-like phenotype of NK cells by triggering a metabolic reprogramming toward glutamine dependence. The decreased α-ketoglutarate/succinate ratio in Ndufa9-deficient NK cells mediated widespread epigenetic reprogramming by inducing the transcriptionally repressive histone mark H3K27me3 on key immune function genes. Resveratrol-mediated NDUFA9 activation or its overexpression enhanced NK cell anti-GBM function by restoring complex I activity. Together, these findings reveal the critical role of mitochondrial complex I activity in NK cells and highlight its potential as an actionable target to enhance NK cell-based immunotherapy for patients with GBM. SIGNIFICANCE: This study reveals that NDUFA9 deficiency in mitochondrial complex I compromises metabolic fitness and impairs the antitumor activity of NK cells in GBM. We identify the mitochondrial complex I subunit NDUFA9 as a key pharmacologically targetable node for NK cell-based immunotherapy in GBM, leveraging metabolic reprogramming to enhance antitumor efficacy. See related commentary by Tiberti et al., p. 1727.