Abstract 6521: Tumor colonization with <i>Candida albicans</i> increases tumor growth and decreases treatment response by influencing tumor hypoxia and immune activity

Abstract Microbes residing in either the gut or inside tumors have been shown to affect tumor growth and therapeutic response in cancer. Our preliminary data supported an association between the presence of Candida fungi within tumors and decreased therapy response and survival of rectal cancer patients. However, whether intratumoral Candida drive, support, or simply inhabit tumors with poor prognoses remains unclear. Here, we identify that C. albicans plays a causal role in modifying tumor physiology and response to treatment. Immune competent C57BL/6 mice bearing MC38 colorectal or LLC lung cancer flank tumors were gavaged with C. albicans or PBS. MC38 mice were treated with 1 fraction of 7.5 Gy radiation and at size endpoint, tumors were stained for fungi and underwent bulk RNA-sequencing. LLC tumors underwent tumor electron paramagnetic resonance monitoring for intratumoral oxygen content, inorganic phosphate, and pH. MC38 cells were cultured in filtered C. albicans conditioned media. Metabolomics was performed on the conditioned media. RNA-sequencing from human tumors from the ORIEN database was analyzed for gene expression related to C. albicans. C. albicans translocated to tumors following oral gavage. The presence of C. albicans reduced radiation efficacy in MC38 tumors and increased LLC tumor growth (p&amp;lt;0.05). LLC tumors from mice gavaged with C. albicans had lower pH and decreased oxygen tension. Transcriptional profiling indicated that colonization of these murine tumors and as well as human samples with C. albicans showed decreased CD8+ T cell activity and increased glycolytic metabolism. Mechanistic studies further showed that MC38 cells grown in the presence of C. albicans metabolites exhibited an increased oxygen consumption rate, and that this conditioned media supported increased mitochondrial beta-oxidation. Here, we show through in vitro assays, murine models, and human samples that C. albicans can directly affect tumor growth and treatment resistance, potentially through generating an immune cold and more hypoxic and acidic environment. These data support experimentation to determine clinical relevance of depletion of C. albicans or related metabolites from tumors to improve clinical outcomes. Citation Format: Dennis Grencewicz, Alexander Loncar, Ruohan Wu, Rebecca Hoyd, Jinghai Wu, Yogita Mehra, Shiva Jahanbahkshi, Sylvain Ferrandon, Matthew Anderson, Martin Benej, Jiangjiang Zhu, Matthew Kalady, David Carbone, Nicholas Denko, ORIEN Microbiome Research Interest Group, Daniel Spakowicz. Tumor colonization with Candida albicans increases tumor growth and decreases treatment response by influencing tumor hypoxia and immune activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6521.