Mitochondria in cancer: unravelling their role in resistance to therapies

Mitochondria are now recognized as central regulators of tumor biology, extending beyond their traditional role in bioenergetics to control cell survival, stress responses, immune signaling, and adaptation to therapeutic pressures. In cancers, mitochondrial plasticity encompasses, in particular, metabolic reprogramming, redox regulation, mitochondrial DNA signaling, mitochondrial dynamics, and quality control mechanisms, enabling tumor cells to adapt to a heterogeneous and challenging microenvironment. However, these alterations are not limited to malignant cells: they also influence the mitochondrial state and functions of various immune cell populations in the tumor microenvironment. The reciprocal interactions between tumor and immune mitochondria, involving metabolic competition, mitochondrial-derived signals, and, more recently, intercellular mitochondrial transfer, can promote immune dysfunction and tumor escape. These mechanisms contribute to resistance to immunotherapies, particularly immune checkpoint blockade, as well as to resistance to certain chemotherapies and targeted therapies. This review integrates these mechanisms around a central concept: mitochondrial plasticity serves as a functional interface linking tumor adaptation, immune suppression, and therapeutic resistance. We also examine mitochondrial vulnerabilities that could be exploited therapeutically, emphasizing the highly context-dependent nature of mitochondrial targeting and the need to preserve mitochondrial functions essential for antitumor immunity. Finally, we discuss mitochondrial heterogeneity, potential biomarkers, and emerging approaches based on single-cell, spatial, CRISPR, and multi-omics technologies, which could enable more precise identification of mitochondrial vulnerabilities and improved patient stratification. Together, these advances pave the way for a transition from nonspecific mitochondrial targeting to context-specific and precision mitochondrial immunotherapy.