Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression.

Mitochondria in natural killer (NK) cells orchestrate a dynamic interplay between energy production and immune regulation, placing them at the forefront of oncogenesis and tumor microenvironment (TME) infiltration. This review unravels the intricate disruptions in mitochondrial dynamics-fission, fusion, and biogenesis-that hypoxia imposes within the TME, culminating in impaired NK cell functionality. Hypoxia-driven mitochondrial fragmentation, mediated by HIF-1α and mTOR-Drp1 signaling, cripples NK cell cytotoxicity, proliferation, and maturation, while elevated ROS levels and metabolic reprogramming bolster tumor immune evasion. The metabolic landscape of the TME adds another layer of complexity, with amino acid depletion significantly hindering NK cell performance. Arginine and leucine deficiencies suppress proliferation and mTOR activation, whereas disrupted glutamine metabolism impairs cMyc-driven metabolic adaptation. Additionally, immunosuppressive catabolites like nitric oxide and L-kynurenine exacerbate NK cell dysfunction by curbing cytokine production and receptor expression. Targeting these metabolic vulnerabilities offers a promising strategy; specifically, interventions aimed at amino acid pathways could simultaneously restrict nutrient availability within the tumor microenvironment and preserve NK cell functionalities. Emerging strategies spotlight the potential of NK cells to induce autophagic death in hypoxic cancer cells, a mechanism that could restore their cytotoxic potential. Furthermore, immune checkpoint pathways, such as PD-1 and CTLA-4, amplify mitochondrial dysfunction, underscoring their therapeutic significance. By addressing hypoxia, metabolic dysregulation, and mitochondrial reprogramming, this review illuminates actionable strategies to reinvigorate NK cell-mediated antitumor responses and pave the way for transformative cancer therapies.