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Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for
Nianxin Zhou1,2,3, Fan Fei4, Lin Tang5
1Department of Neurosurgery, West China Hospital, State Key Laboratory of Biotherapy, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China.
Abstract:
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.
Insights
Natural killer (NK) cells combat glioblastoma (GBM) poorly due to impaired mitochondrial function. Restoring mitochondrial complex I activity via NDUFA9 enhances NK cell anti-GBM efficacy, offering a new immunotherapy target.
Area of Science:
- Immunology
- Cancer Biology
- Mitochondrial Biology
Background:
- Immunotherapies, including immuno-oncology, have shown limited success in treating glioblastoma (GBM).
- Natural killer (NK) cells from GBM patients exhibit diminished oxidative phosphorylation and mitochondrial complex I activity, hindering their anti-tumor functions.
Purpose of the Study:
- To investigate the role of mitochondrial complex I activity in NK cell function in the context of GBM.
- To identify specific molecular targets for enhancing NK cell-based immunotherapy against GBM.
Main Methods:
- Multiomics profiling to identify key mediators of NK cell metabolic fitness.
- Genetic manipulation (Ndufa9 knockout) to assess the impact on NK cell function.
- Analysis of metabolic reprogramming, epigenetic changes (H3K27me3), and anti-tumor efficacy.
- Investigating the effect of resveratrol and NDUFA9 overexpression on NK cell activity.
Main Results:
- NDUFA9, a subunit of mitochondrial complex I, was identified as critical for NK cell metabolic fitness and patient outcomes.
- Ndufa9 deficiency in NK cells led to impaired mitochondrial function, metabolic reprogramming towards glutamine dependence, and reduced anti-tumor efficacy.
- Decreased α-ketoglutarate/succinate ratio in Ndufa9-deficient NK cells induced epigenetic reprogramming via H3K27me3, suppressing immune gene expression.
- NDUFA9 activation or overexpression restored NK cell mitochondrial function and enhanced anti-GBM activity.
Conclusions:
- Mitochondrial complex I activity, specifically mediated by NDUFA9, is crucial for NK cell function and anti-GBM immunotherapy.
- Targeting NDUFA9 and restoring mitochondrial complex I activity represents a promising strategy to improve NK cell-based therapies for glioblastoma.
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