Ping Lai, Lei Liu, Nicolò Pernigoni, Yingxi Du, Daniele Braga, Martina Troiani, Giuseppe Attanasio, Yuxin Li, Pan Song, Emiliano Pasquini, Tanja Rezzonico Jost, Xiaowen Huang, Martino Maddalena, Simone Mosole, Andrea Rinaldi, Giovanna Pecoraro, Martino Pedrani, Aurora Valdata, Nicolò Bancaro, Luisa Maraccani, Alessandra De Giani, Wei Yuan, Lewis Gallagher, Khobe Chandran, Penny Flohr, Pasquale Rescigno, Giuseppe Reitano, Alessandro Morlacco, Fabrizio Dal Moro, Isabella Giacomini, Monica Montopoli, Matteo Brunelli, Serena Pedron, Ricardo Pereira Mestre, Raad Z Gharaibeh, Christian Jobin, Silke Gillessen Sommer, Johann de Bono, Andrea Alimonti
Recent studies demonstrate that the gut mycobiota plays a key role in several tumors. However, the contribution of commensal fungi to prostate cancer initiation and progression remains understudied. Here we find that Nakaseomyces glabratus is enriched in fecal, blood and tumor samples of patients with castration-resistant prostate cancer, correlating with patients' poor overall survival. Oral administration of N. glabratus to castrated mice accelerated cancer progression by promoting infiltration and activation of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, androgen deprivation therapy increases intestinal permeability, resulting in the leakage of N. glabratus from the gut to the tumor site, activating PMN-MDSCs via the Dectin-2 receptor. Treatment of mice with a negatively charged intestinal hydrogel blocks N. glabratus translocation to tumor, reducing PMN-MDSCs' intratumoral infiltration and activation. Taken together, these findings reveal that the gut-to-tumor translocation of N. glabratus contributes to endocrine resistance in prostate cancer by enhancing the immunosuppressive microenvironment of these tumors.