Mitochondrial-targeted therapeutics in oral squamous cell carcinoma: molecular and therapeutic implications

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy characterized by frequent resistance to conventional chemoradiation, a phenotype increasingly linked to mitochondrial dysregulation. Accumulating evidence suggests that mtDNA mutational burden/signatures and broader metabolic reprograming may contribute to this resistant phenotype, but their predictive value and causal roles remain incompletely defined. Unlike prior syntheses that primarily catalog downstream phenotypic outcomes such as apoptosis or generalized oxidative stress, this comprehensive narrative review adopts a mechanism-driven framework centered on organelle-specific vulnerabilities and translationally relevant delivery strategies. We evaluate candidate therapeutics targeting electron transport chain (ETC) function, the mitochondrial apoptotic machinery, and redox homeostasis, while distinguishing OSCC-specific evidence from broader head and neck or pan-solid-tumor data. We further examine key barriers to clinical implementation, including intratumoral heterogeneity, limited tumor-selective mitochondrial delivery, and the lack of validated predictive and pharmacodynamic biomarkers. Overall, this review provides a cautious translational roadmap for testing mitochondria-directed strategies in OSCC and highlights priorities for biomarker-enriched, mechanism-informed clinical development.