Mitochondrial impairment and mTORC1 signalling exhaustion define NK Cell dysfunction progression in melanoma.

Cutaneous melanoma is a highly metastatic cancer which had limited treatment options until the advent of immune checkpoint inhibitors (ICI); however, only around 50% of patients respond. Natural killer (NK) cells are potent cytotoxic and cytokine producing lymphocytes which present a promising avenue for immunotherapy. However, the progressive dysfunction of NK cells during cancer development represents a major barrier to effective autologous therapies. This study investigated the metabolic and functional plasticity of circulating NK cells during melanoma progression from Stage III lymph node positive and Stage IV metastatic melanoma. Stage III patient NK cells displayed reduced mitochondrial mass, fragmented morphology and dysregulated mTORC1 activity, accompanied by impaired cytotoxicity. Stage IV patients showed severe mitochondrial fragmentation, altered mTORC1 activation and markedly reduced cytokine responsiveness. Pharmacologic restoration of mTORC1 activity using MHY1485 rescued IFN-y production in Stage III but not Stage IV patient NK cells, suggesting stage-dependent differences in metabolic responsiveness. Collectively, these findings indicate progressive metabolic and functional impairment of circulating NK cells as melanoma advances and highlight a potential window for therapeutic intervention earlier in disease progression.