Mitochondrial metabolic plasticity in cancer: hybrid bioenergetic states and translational targeting in surgical oncology.

Abstract

Mitochondrial metabolism is increasingly recognized as an active determinant of tumor growth and cancer-cell adaptation rather than solely a source of cellular energy. Mitochondrial metabolism supports tumor anabolism, while mitochondrial DNA (mtDNA) alterations can affect respiratory chain function, redox homeostasis, and adaptation to changing tumor environments. At the same time, tumor metabolism is heterogeneous and flexible and cannot be explained by a uniform Warburg model. Tumor cells may use glycolysis, oxidative phosphorylation (OXPHOS), or hybrid glycolysis/OXPHOS states, with the relative contribution of these pathways varying across tumor types, tumor regions, microenvironmental conditions, and therapeutic pressure. This metabolic flexibility may contribute to tumor progression, metastasis, and treatment resistance. In this review, we examine mitochondrial metabolic phenotypes in cancer and their relevance to therapeutic targeting and surgical oncology. We discuss OXPHOS-dependent tumor states, mitochondrial DNA mutations, mitochondrial dynamics, reactive oxygen species, mitochondrial membrane potential, and mitochondrial regulation of intrinsic apoptosis. We further evaluate therapeutic strategies targeting these vulnerabilities, including OXPHOS inhibitors, BCL-2 family inhibitors, ROS modulators, mitochondrial dynamics modulators, mitochondrial genome-editing approaches, and emerging mitochondria-directed immunotherapies. Clinical evidence indicates that broad mitochondrial-targeted interventions may be limited by toxicity, narrow therapeutic windows, limited efficacy, or lack of benefit in unselected populations, supporting the need for metabolic phenotype classification, biomarker-guided patient selection, and rational combination strategies. Particular emphasis is placed on the potential integration of mitochondrial targeting with surgical oncology. Metabolic heterogeneity within tumors and the tumor microenvironment may influence treatment response, residual disease, and recurrence. Emerging approaches such as mass spectrometry imaging, single-cell sequencing, and spatial transcriptomic analysis may allow metabolic features to be mapped within anatomically defined regions of surgical specimens and linked to specific malignant, stromal, and immune-cell populations. Such approaches may help identify OXPHOS-dependent, glycolytic, and metabolically flexible tumor populations and provide clinically relevant biomarkers for treatment selection and monitoring. Overall, mitochondrial vulnerabilities represent a context-dependent therapeutic opportunity rather than a universal metabolic target. Better characterization of mtDNA alterations, metabolic plasticity, spatial heterogeneity, and tumor-specific metabolic dependencies will be important for developing biomarker-guided mitochondrial therapies and for determining how these interventions can be safely integrated into neoadjuvant, adjuvant, and perioperative cancer care.