Fungal Colonization by <i>Malassezia globosa</i> Promotes Breast Cancer Progression and M2 Macrophage Polarization Through the MBL‐C3a–C3aR Signaling Pathway

Fungal colonization is a known carcinogenic accomplice in lung and colon cancer but has not been implicated in breast cancer. Here, we attempt to explore the mechanism behind fungal colonization and carcinogenesis by Malassezia globosa in breast cancer. To begin with, we found an increased abundance of the fungus in tumor tissues of breast cancer patients and the fungal inhibitor Amphotericin-B impeded tumor growth in patient-derived breast cancer xenograft models. On the other hand, Malassezia globosa enhanced the proliferative, migratory, and invasive abilities of breast cancer cells, and facilitated tumor growth in vivo. The positive effect of Malassezia globosa on tumor growth occurred via M2 macrophage polarization resulting in the activation of the pro-inflammatory MBL-C3a-C3aR signaling cascade which was reversed with the knockout of MBL expression. The proliferative, migratory, and invasive capacities of breast cancer cells were enhanced by culture medium from Malassezia globosa-treated THP-1 cells, which were rescued by a C3aR antagonist. In conclusion, Malassezia globosa activates MBL-C3a-C3aR signaling to trigger M2 macrophage polarization, promoting breast cancer progression and this study unravels a novel paradigm for breast cancer treatment.