Candida albicans infiltrates colon and rectal cancers causing therapeutic resistance and decreased survival
The microbiome is increasingly recognized as a modifier of cancer progression and therapy response, yet the role of intratumoral fungi remains poorly defined. Here, we identify Candida albicans colonization within human colorectal tumors as a predictor of reduced survival and impaired radiation response. Leveraging the Oncology Research Information Exchange Network (ORIEN) cohort, we show that high intratumoral Candida burden is associated with decreased survival across multiple gastrointestinal cancers, with the strongest treatment-specific effect in rectal cancer patients receiving radiotherapy. This observation was validated in independent rectal cancer cohorts using RNA sequencing and quantitative PCR. In immune-competent murine colorectal cancer models, oral gavage of C. albicans resulted in intratumoral colonization, accelerated tumor growth, and radiation resistance, effects not observed with Saccharomyces cerevisiae or PBS controls. Colonized tumors exhibited increased hypoxia, altered metabolic and transcriptional programs, and distinct expression of genes linked to cytokine signaling and cell survival. Hypoxia conditioned C. albicans secreted metabolites that directly conferred radiation resistance to colorectal cancer cells in vitro, implicating a cancer cell intrinsic mechanism independent of immune signaling. Untargeted metabolomics revealed enrichment of nucleosides and lipid oxidation intermediates under hypoxia, suggesting that C. albicans metabolites may provide substrates facilitating tumor recovery after irradiation. These findings establish C. albicans as a causal modifier of tumor biology and radiation response, highlighting intratumoral fungi as future potential therapeutic targets. Modulating fungal colonization or metabolism may improve radiotherapy outcomes and broaden our understanding of interactions between microbes and tumors.