Left panel: targeting mitochondrial metabolic pathways, including fatty acid oxidation, the electron transport chain (ETC), glutamine metabolism, the tricarboxylic acid (TCA) cycle, reactive oxygen species (ROS) generation, and one-carbon metabolism, could support standard antineoplastic therapies to arrest tumor progression. Right panel: treatment with m-3M3FBS culminates with massive cell death, through a series of events that comprehends: (1) Ca2+ efflux from the ER; (2) mitochondrial Ca2+ accumulation; (3) inner mitochondrial membrane (IMM) permeabilization; (4) outer mitochondrial membrane (OMM) rupture; (5) release of mitochondrial factors into the cytoplasm. Created with BioRender.com.