Mitochondrial Ca2+ signaling: A metabolic rheostat defining tumor and immune cell fate.

Mitochondrial calcium (mtCa2+) has long been framed as a bioenergetic regulator, yet evidence redefines it as a relevant immunometabolic switch. Within the tumor microenvironment, the mitochondrial calcium uniporter (MCU) complex and the NCLX-TMEM65 efflux axis maintain a 'Goldilocks zone' of Ca2+ homeostasis. This can be exploited by cancer cells to sustain oxidative phosphorylation and tricarboxylic acid-derived oncometabolite production, including succinate, fumarate, and 2-hydroxyglutarate, while imposing ionic and nutrient constraints on infiltrating immune cells. Chronic mtCa2+ overload in effector T cells drives mitochondrial dysfunction and exhaustion, while oxidative phosphorylation-dependent Ca2+ flux enforces the acquisition of an immunosuppressive profile in macrophages. Disrupting these tumor-immune ionic imbalances through selective MCU modulation or efflux pathway targeting offers a strategy to restore immune surveillance and/or enhance immune checkpoint inhibitor therapies.