Tumor metabolic plasticity in therapy resistance: from the Warburg effect to mitochondrial hijacking

The clinical efficacy of targeted cancer therapies is persistently undermined by the emergence of acquired resistance. While secondary genetic mutations are well-characterized, increasing evidence implicates non-genetic metabolic reprogramming as a primary driver of survival during the initial phase of treatment. This review elucidates the concept of "Metabolic Shapeshifters"-specifically, drug-tolerant persister cells (DTPs) that dynamically adapt their bioenergetic machinery to evade therapeutic stress. We examine the plasticity between the classical Warburg Effect and the Reverse Warburg Effect, describing how DTPs shift from a glucose-addicted proliferative state to a quiescent phenotype strictly reliant on mitochondrial oxidative phosphorylation (OXPHOS) and fatty acid oxidation. Crucially, we highlight a paradigm shift from intracellular reprogramming to intercellular "organelle parasitism." Recent breakthroughs demonstrate that DTPs actively hijack functional mitochondria from infiltrating immune cells and the stromal network via tunneling nanotubes (TNTs). This predatory behavior not only restores the tumor's respiratory capacity but also induces metabolic exhaustion in T cells, thereby orchestrating immune evasion. Finally, we delineate emerging therapeutic strategies designed to dismantle this metabolic fortress. By targeting the "Achilles' heel" of mitochondrial dependency, disrupting the physical infrastructure of organelle hijacking, and revitalizing immunometabolism, we propose a multi-pronged framework to eradicate DTPs and prevent clinical relapse.