Prostate cancer: new study reveals a gut-to-tumor pathway driving progression and therapy resistance
Institute of Oncology Research
A new study led by Prof. Andrea Alimonti, Group Leader of the Molecular Oncology Research Group at the Institute of Oncology Research (IOR, affiliated to USI and member of Bios+) has identified a gut-to-tumor pathway through which the commensal fungus Nakaseomyces glabratus enchances the immunosuppressive tumor microenvironment that favours prostate cancer progression.
The study shows that N. glabratus, one of the most common fungi involved in nosocomial infections, can migrate from the intestine to prostate tumors following androgen deprivation therapy. Once inside the tumor, the fungus activates immunosuppressive myeloid cells, promoting cancer progression and resistance to androgen-targeted therapy.
Background
In prostate cancer, androgen-deprivation therapy (ADT)—which suppresses androgen receptor signaling, the main driver of tumor growth—is a cornerstone of treatment. Yet many patients eventually develop resistance and progress to castration-resistant prostate cancer (CRPC), which is associated with poor outcomes. While gut bacteria have been intensively studied in prostate cancer, the role of the gut mycobiome—the community of commensal fungi living in the intestine—has remained largely unexplored.
From the gut to the tumor
Dr. Ping Lai, Dr. Lei Liu and their colleagues discovered that DNA from Nakaseomyces glabratus (N. glabratus), a commensal yeast formerly known as Candida glabrata, is enriched in fecal, blood and tumor samples from patients with CRPC. Among all the fungal species detected in fecal samples, N. glabratus was the only one significantly associated with worse overall survival in the clinic.
In mouse models, oral administration of N. glabratus accelerated prostate tumor growth only in surgically castrated mice. The fungus promoted the infiltration and activation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), a population of immune cells that suppress anti-tumor immunity.
A new perspective on endocrine resistance
The team showed that androgens help maintain the intestinal barrier. ADT weakens this barrier, allowing N. glabratusto pass from the intestine into the bloodstream and reach prostate tumors. There, the fungus engages the Dectin-2 receptor on myeloid cells, activating PMN-MDSCs, which in turn produce Activin A—a factor that reactivates androgen receptor signaling in tumor cells and fuels disease progression.
This mechanism provides a possible explanation for how a microorganism that normally resides in the intestine can influence the response of a distant tumor to endocrine therapy. The study therefore places the intestinal barrier and tumor-associated mycobiota within the broader biological network underlying prostate cancer progression.
Potential therapeutic implications
Importantly, the researchers found that blocking the gut-to-tumor migration of N. glabratus could reduce its tumor-promoting effects. In castrated mice bearing prostate tumors, an orally administered intestinal hydrogel reduced fungal translocation, decreased the infiltration of PMN-MDSCs into tumors and attenuated tumor growth.
“These findings reveal an unexpected connection between androgen signaling, the intestinal barrier and the fungal microbiome,” says Prof. Andrea Alimonti, whose group led the study. “They suggest that the gut may influence prostate cancer progression not only through bacteria, but also through fungi that can reach the tumor and reshape its immune environment.”
Further studies in larger patient cohorts will be required to determine how frequently this pathway occurs in patients and whether preventing fungal translocation or targeting MDSCs could offer new avenues for future therapeutic development.
From IOR research to an independent scientific career
The publication also marks an important milestone in the career of Dr. Ping Lai, one of the study’s first authors. Dr. Lai conducted this work during his time at IOR before returning to China to establish his independent laboratory at Soochow University in Suzhou, where he has been appointed Principal Investigator and Assistant Professor.
This new role opens an exciting chapter in his scientific career while creating new opportunities to strengthen collaboration between IOR and research institutions in China.
The study reflects not only the scientific discoveries emerging from IOR, but also the institute’s commitment to supporting the development of the next generation of cancer researchers.
About the study
The full study is published in Nature Cancer and is available at https://www.nature.com/articles/s43018-026-01229-9
