Abstract 63: Intratumoral Candida albicans associates with hypoxia and poor outcomes in non small cell lung cancer (NSCLC).

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Abstract Resistance to radiation, chemotherapy, and immunotherapy remains a major challenge in non-small cell lung cancer (NSCLC), and emerging evidence suggests tumor-resident microbes may influence therapeutic response. To address this, we combined patient-level modeling with mechanistic studies in preclinical models. We first analyzed RNA-sequencing data from 2,156 NSCLC tumors collected under the Total Cancer Care Protocol (NCT03977402) within the ORIEN network using a contamination-aware pipeline to quantify intratumoral Candida albicans (CA) and assess its impact on treatment outcomes. We developed MEC-TX (Mechanistic Clustering Treatment), a digital-twin framework that compares patients receiving similar treatment regimens differing only by CA burden. CA was detected in ∼55% of tumors; high CA burden was associated with significantly shorter overall survival (hazard ratio 1.6, p < 0.01), and similar trends were observed in radiation- and chemotherapy-treated cohorts defined by MEC-TX. After adjusting for clinical covariates (age, sex, stage, BMI), CA remained an independent predictor of poor survival, underscoring MEC-TX’s ability to isolate biologically meaningful signals. Transcriptomic profiling revealed CA-high tumors had elevated hypoxia-related gene expression (p = 0.0045), suggesting a link between fungal infiltration and tumor microenvironment. To test this, we implanted Lewis lung carcinoma cells into syngeneic C57BL/6 mice and gavaged them with CA, Blautia obeum (commensal control), or saline (vehicle control). CA-gavaged tumors were significantly larger (p = 0.0108) and exhibited lower pH (p = 0.024) and reduced intratumoral pO2 (p = 0.051) compared to controls, as measured by EPR oximetry, after adjusting for tumor size, supporting CA’s role in creating a hypoxic, therapy-resistant niche. In vitro, CA-conditioned media conferred radioresistance across multiple cell lines (p = 0.001), implicating secreted molecules as drivers of this phenotype. Collectively, these findings reveal a novel mechanism by which intratumoral fungi promote hypoxia and treatment resistance, providing a strong rationale for microbiome-informed strategies to overcome hypoxia-driven resistance and improve precision oncology. Citation Format: Dipankor Chatterjee, Dennis J. Grencewicz, Alexander Loncar, Ruohan Wu, Alex Samouilov, Sylvain Ferrandon, McKenzie Kreamer, Yogita Mehra, Aspen Carson, Rebecca Hoyd, Shiva Jahanbakhshi, Fouad Choueiry, Matthew Anderson, Martin Benej, Dustin Bosch, Jiangjiang (Chris) Zhu, Jinghai Wu, Thèrése Bocklage, Martin McCarter, Ahmad Tarhini, Bodour Salhia, Christopher A. Moskaluk, Gregory Riedlinger, Song Yao, Ashiq Masood, Sheetal Hardikar, Mmadili N. Ilozumba, Cornelia M. Ulrich, Abdul Rafeh Naqash, Carlos H.F. Chan, Craig D. Shriver, Dinesh Pal Mudaranthakam, Aaditya Pallerla, Michelle Churchman, Robert J. Rounbehler, Laura Chambers, Matthew F. Kalady, Nicholas C. Denko, David P. Carbone, Dan Spakowicz. Intratumoral Candida albicans associates with hypoxia and poor outcomes in non small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 63.

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