Malassezia restricta-Derived Extracellular Vesicles Drive Ovarian Cancer Progression Through JAK2/STAT3-Mediated M2...

The intratumoural mycobiome is a critical constituent of the tumour microenvironment; however, its specific impact on epithelial ovarian cancer (EOC) progression and the underlying molecular mechanisms remain largely elusive. In this study, internal transcribed spacer 1 (ITS1) sequencing revealed a significant enrichment of Malassezia in EOC tissues compared with epithelial borderline ovarian tumours, with its abundance positively correlated with disease progression. Subsequent intratumoural microbiota transplantation and mono-colonisation in a murine EOC model demonstrated that Malassezia restricta substantially accelerated tumour growth and increased M2 macrophage infiltration. Furthermore, in vitro assays established that M. restricta-derived extracellular vesicles (MrEVs) play a pivotal role in inducing M2 macrophage polarisation. Mechanistically, both in vitro and in vivo data showed that MrEVs activate the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signalling pathway, thereby driving M2 polarisation and tumour malignancy. Collectively, these findings identify M. restricta as a pro-tumourigenic fungus in EOC and uncover a previously unrecognised fungal-immune axis that promotes tumour progression. This study provides new insight into the oncogenic role of tumour-resident fungi and highlights the M. restricta EV-JAK2/STAT3 axis as a potential therapeutic target for immune modulation.