Cancer Cells Hijack Fibroblasts by Donating Mitochondria via Protein MIRO2

The tumor microenvironment is shaped not only by cancer cells themselves but by surrounding stromal cells, particularly cancer-associated fibroblasts (CAFs), which actively promote tumor progression. However, the mechanisms by which normal fibroblasts are converted into these pro-tumorigenic CAFs have remained incompletely understood. This study, published in Nature Cancer in 2025, identifies mitochondrial transfer from cancer cells to fibroblasts as a previously unrecognized driver of CAF differentiation.

Using cocultures of human primary skin fibroblasts (HPFs) with multiple cancer cell lines—including A431 vulvar carcinoma, MDA-MB-231 breast cancer, and PANC1 pancreatic cancer cells—the researchers demonstrated that cancer cells transfer mitochondria to adjacent fibroblasts through tunneling nanotubes (TNTs), thin actin-containing membranous bridges between cells. Transfer was confirmed using MitoTracker labeling, species-specific mitochondrial DNA detection, single-nucleotide polymorphism analysis, and real-time holotomographic live imaging. The transfer was dependent on actin polymerization and exocyst complex components SEC3/SEC5, but not on gap junctions or microtubules.

Fibroblasts that received cancer cell mitochondria underwent metabolic reprogramming, including increased oxidative phosphorylation and altered metabolic flux, and acquired hallmark CAF features: upregulation of alpha-smooth muscle actin (α-SMA), FAP, and other CAF markers, along with secretion of a pro-tumorigenic secretome and remodeled matrisome enriched in tumor-supportive extracellular matrix components. These mitochondria-recipient fibroblasts significantly promoted tumor formation and growth in preclinical mouse xenograft models, confirming functional CAF activity.

Mechanistically, the study identified MIRO2 (RHOT2), a mitochondrial Rho GTPase involved in mitochondrial trafficking along the cytoskeleton, as the key molecular driver of this transfer. Genetic depletion of MIRO2 in cancer cells—but not in fibroblasts—specifically blocked mitochondrial transfer, prevented CAF differentiation, and substantially suppressed tumor growth in vivo. MIRO1, the closely related paralog, did not have the same effect, highlighting MIRO2's unique role. Crucially, MIRO2 was found to be significantly overexpressed in tumor cells at the invasive leading edge of human epithelial skin cancers compared to interior tumor cells or normal epithelium, underscoring the clinical relevance of this mechanism.

These findings reframe our understanding of tumor-stroma crosstalk: rather than responding passively to secreted signals, fibroblasts can be actively reprogrammed through organelle-level communication. Targeting MIRO2 or the TNT-mediated mitochondrial transfer pathway could represent a novel therapeutic strategy to disrupt CAF formation and the pro-tumorigenic microenvironment across multiple cancer types.