Abstract

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.

Breast tumors can reshape the fat cells around them, creating an environment that helps cancer cells survive and resist chemotherapy. Researchers at UNIST and the National Cancer Center (NCC) have identified a mitochondrial protein that helps drive this transformation—and shown in mice that blocking it can make tumors more responsive to treatment.

Led by Professor Byoung Heon Kang of the Department of Biological Sciences at UNIST and Professor Sun-Young Kong of NCC, the team found that TRAP1 plays a key role in converting normal fat cells into cancer-associated adipocytes (CAAs). These altered cell release factors that support tumor growth and protect cancer cells from chemotherapy.

The researchers found that TRAP1 sustains mitochondrial energy production in fat cells, keeping the mTOR–PPARγ pathway active and allowing them to acquire cancer-supporting properties. Blocking TRAP1 disrupts mitochondrial function and activates AMPK, an energy sensor that suppresses this transformation. In tissue samples from 31 patients with breast cancer, TRAP1 expression in fat surrounding tumors was 3.03 times higher than in normal adipose tissue.

The team also identified complement factor D (CFD) as an important link between the altered fat cells and cancer cells. CAAs secrete CFD, which activates survival signals in breast cancer cells and makes them less susceptible to chemotherapy. Blocking this TRAP1-driven communication reduced that protective effect.

In mice, genetically removing TRAP1 suppressed the transformation of adipocytes and reduced tumor weight by as much as 56% compared with controls. Drug-based inhibition produced similar results: combining the TRAP1 inhibitor gamitrinib with cisplatin reduced tumor weight by 76% compared with untreated mice. Another inhibitor, SB-U015, also enhanced the effects of cisplatin and paclitaxel without evident toxicity in the experimental models.

“Our study shows how adipocytes surrounding breast tumors can contribute to chemotherapy resistance,” said Professor Kong. “Further studies are needed to evaluate the clinical potential of TRAP1 inhibitors, not only for patients who respond poorly to existing treatments but also for cancers that develop in close contact with adipose tissue, including ovarian, pancreatic, and prostate cancers.”

Professor Kang added, “These findings suggest that the cells surrounding a tumor can be important therapeutic targets alongside the cancer cells themselves. By disrupting the metabolic changes in nearby adipocytes, we may be able to improve the effectiveness of existing anticancer drugs.”

Professor Kang has transferred the technology arising from the research to SmartinBio, a UNIST faculty startup, where further development of anticancer drug candidates is underway.

The study was co-first authored by Dr. Nam Gu Yoon and Dr. So-Yeon Kim of UNIST and published online in Signal Transduction and Targeted Therapy (STTT) on July 28, 2026. The research was supported by the National Research Foundation of Korea (NRF), the National Cancer Center, and the Korea Drug Development Fund (KDDF).

Journal Reference

Nam Gu Yoon, So-Yeon Kim, So-Youn Jung,  et al ., “The pro-tumorigenic functions of cancer-associated adipocytes are dependent on the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1,”  STTT.,  (2026).