Effect of Nakaseomyces glabratus on BM-MDSCs

Recent studies demonstrate that the gut mycobiota plays a key role in several tumors’ development. However, the contribution of commensal fungi to prostate cancer initiation and progression remains understudied. Here, we find that Nakaseomyces glabratus (N.glabratus), is enriched in fecal, blood, and tumor samples of a subset of CRPC patients, positively correlating with patients’ poor overall survival. Oral administration of N.glabratus to castrated mice accelerated CRPC development by controlling polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, androgen deprivation therapy (ADT) increases intestinal permeability, resulting in the leakage of N.glabratus from the gut to the tumor site, where it activates PMN-MDSCs by binding to the Dectin-2 receptor. Treatment of mice with a negatively charged hydrogel blocks N.glabratus translocation to the tumor site, reducing PMN-MDSCs intratumoral infiltration and activation. Taken together, these findings reveal that the gut-to-tumor translocation of commensal fungi contributes to endocrine resistance in CRPC by enhancing the immunosuppressive microenvironment of these tumors.