Candida albicans drives colorectal cancer progression by inducing hypoxia signaling

Colorectal cancer (CRC) is the third leading cause of cancer-related mortality worldwide. Gut microbiota, including fungal species, are increasingly implicated in CRC progression, while the molecular mechanisms underlying host-fungal interactions in this context remain poorly understood. Here, we show that Candida albicans (C. albicans) activates pro-metastatic signaling pathways, MAPK and NF-κB, leading to upregulation of oncogenic transcription factors c-Jun and c-Myc. This cascade stabilizes and activates hypoxia-inducible factor 1α (HIF-1α), a central regulator of tumor metabolic reprogramming and angiogenesis, ultimately fostering a pro-tumorigenic microenvironment. Mechanistically, we identify candidalysin, a secreted peptide toxin of C. albicans, as a critical effector that engages epidermal growth factor receptor (EGFR) and toll-like receptor 2 (TLR2) in a species- and cancer cell type-dependent manner. These findings are further supported by patient-derived colonic organoids. Collectively, our study delineates a C. albicans-EGFR/TLR2-ERK/NF-κB-HIF-1α axis that promotes hypoxia-like responses in CRC, revealing a previously underappreciated role of fungal pathogens in shaping the tumor microenvironment and offering potential targets for therapeutic interventions.