The Pro-Tumorigenic Functions of Cancer-Associated Adipocytes Are Dependent on the Mitochondrial Chaperone Tumor Necrosis Factor Receptor-Associated Protein 1

Adipocytes are essential stromal components of the tumor microenvironment (TME) in breast cancer that play pivotal roles in cancer progression and chemoresistance. In close proximity to tumor cells, they undergo phenotypic reprogramming into cancer-associated adipocytes (CAAs), characterized by multilocular lipid droplets, increased mitochondrial content, and elevated expression of uncoupling protein 1 (UCP1). Although these features superficially resemble those of beige adipocytes, they do not recapitulate classical thermogenic programming, reflecting a unique metabolic adaptation driven by the TME. Here, we identified tumor necrosis factor receptor-associated protein 1 (TRAP1), a mitochondrial paralog of HSP90, as a central regulator of the transition of adipocytes into CAAs. TRAP1 was highly upregulated in CAAs and was required to drive a tumor-associated adipocyte secretory program, including the adipokine complement factor D (CFD). Genetic and pharmacological TRAP1 inhibition destabilized the mitochondrial electron transport chain, reduced cellular respiration, and activated the energy sensor AMPK. This subsequently suppressed mTOR and PPARγ signaling, effectively abrogating adipocyte reprogramming and diminishing pro-tumorigenic adipokine secretion. Crucially, this CAA-secreted CFD promoted cancer cell survival and chemoresistance via C3aR-AKT/ERK signaling, and blocking this TRAP1-mediated crosstalk profoundly sensitized breast tumors to chemotherapy in vivo. Collectively, these findings identify TRAP1 as a master regulator of adipocyte transdifferentiation within the TME, offering a novel strategy to restrict tumor growth and overcome drug resistance in breast cancer.