Resensitizing drug-resistant cancers by co-targeting apoptosis and mitochondrial stress pathway.

Therapeutic resistance is a major barrier to durable cancer control in contemporary oncology practice. Despite extensive studies on individual cell death pathways and mitochondrial stress responses, a comprehensive framework describing how mitochondrial organization contributes to the coordination of multiple regulated cell death programs and therapeutic resistance remains insufficiently defined. This review examines resistance as malignant cells evade regulated cell death and adapt to mitochondrial stress. Mitochondria are framed as integrative hubs that link bioenergetics, redox regulation, metabolic flexibility, and stress signaling to apoptotic competence. It also describes how apoptosis connects with other death programs through mitochondrial compartmentalization. Signals from the matrix, inner membrane, and cristae, intermembrane space, and outer membrane influence ferroptosis, necroptosis, mitochondrial permeability transition-driven necrosis, and immunogenic cell death. Stress-response pathways are highlighted as interfaces between mitochondrial dysfunction and fate decisions, including the OMA1-DELE1-heme-regulated inhibitor kinase axis that activates the integrated stress response and ATF4-dependent transcription. Translationally, the review proposes a co-targeting framework that pairs apoptosis-directed therapies, especially BH3 mimetics, with interventions that destabilize mitochondrial homeostasis or tune stress signaling. Examples include electron transport chain inhibitors, integrated stress response modulators, and compartment-targeted strategies that alter cristae remodeling, calcium flux, or cardiolipin oxidation.