Mitochondrial metabolic reprogramming in colorectal cancer: mechanisms of resistance and future clinical interventions

Colorectal cancer (CRC) is a leading cause of global cancer mortality, with therapeutic resistance constituting a major barrier to sustained clinical benefit. Mitochondrial metabolic reprogramming has emerged as a central adaptive mechanism that enables CRC cells to withstand hypoxia and therapeutic pressure, while concurrently driving resistance to chemotherapy, targeted agents, and immunotherapy. In this Review, we explore how mitochondrial metabolism contributes to therapeutic resistance, with particular emphasis on metabolic plasticity, redox balance, and organelle quality control. We also assess enabling technologies such as spatial transcriptomics, proteomics, and patient-derived organoids, and discuss their translational relevance in stratifying metabolic vulnerabilities and informing individualized therapies. Targeting mitochondrial rewiring represents a compelling strategy to overcome resistance and drive progress toward personalized CRC therapy.