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

## TL;DR

This paper explores how cancer cells adapt their metabolism to survive treatment, shifting from one energy source to another and even stealing mitochondria from immune cells to evade therapy.

## Contribution

The paper introduces the concept of 'Metabolic Shapeshifters' and highlights intercellular mitochondrial hijacking as a novel mechanism of therapy resistance.

## Key findings

- Drug-tolerant persister cells switch from glycolysis to mitochondrial OXPHOS and fatty acid oxidation to survive therapy.
- Tumor cells hijack mitochondria from immune cells via tunneling nanotubes, enabling metabolic survival and immune evasion.
- Targeting mitochondrial dependency and disrupting organelle transfer offers new therapeutic strategies to combat resistant cancer cells.

## Abstract

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.