Mitochondrial Energy Metabolism in Cancer, Immunoregulation and Antitumour Response

Mitochondria are the cells' powerhouse, a dogma that has guided research for decades. While this bioenergetic view is accurate, it fails to capture the extra-metabolic signalling functions of mitochondria, as well as the complexity of mitochondrial homeostasis and its contribution to disease pathogenesis, particularly in cancer. In this chapter, we review the multifaceted role of mitochondria in cancer and immunity, starting from the bioenergetic point of view and expanding to metabolic reprogramming in cancer, their role in signalling regulation, immune cell homeostasis and promising immunotherapeutic approaches to treat cancer. We highlight how metabolic flexibility, including the coordinated activation of glycolysis and oxidative phosphorylation (OxPhos), rewiring of the tricarboxylic acid (TCA) cycle, and regulation of redox balance, underpins tumour growth and immune evasion. Special attention is given to mitochondrial-derived signals, such as reactive oxygen species (ROS), lactate shuttling, and mitochondrial DNA (mtDNA) release, that modulate both innate and adaptive immune responses within the tumour microenvironment (TME). Moreover, we further elucidate mitochondrial energy metabolism as a pivotal cornerstone of both cancer prevention and treatment, emphasising its therapeutic potential in overcoming immune suppression and enhancing the efficacy of interventions such as immune checkpoint blockade, adoptive T-cell transfer, and natural killer cell-based therapies.