Abstract B011: Harnessing epigenetic and metabolic biomarkers for targeted immunotherapy in colorectal cancer: Advances in precision medicine for solid tumors

Abstract Cancer cells are defined by rapid, unchecked proliferation, a hallmark that distinguishes them from normal cells. This aggressive growth often leads to a nutrient- and oxygen-deprived tumor core, where limited blood supply cannot sufficiently reach. While most cells typically undergo cell death under such glutamine-deficient conditions, a subset of cancer cells survives through specific epigenetic modifications, facilitating metastatic progression. Using spatial transcriptomics analysis, we reveal that colorectal cancer cells exploit the downregulation of GLS2 expression to avoid ferroptosis and support metastasis in the tumor's glutamine-starved core. We further identified an increase in H3K27Me3 modification as a key epigenetic driver enabling these adaptations in glutamine-deficient regions. This hypothesis has been validated in in vivo mouse colon cancer models and in patient samples compared with healthy controls, reinforcing its translational relevance. Importantly, by employing amino acid profiling through 19F NMR spectroscopy, we identified key biomarkers in the tumor microenvironment that may enhance response to immunotherapy and overcome current therapeutic resistance. These findings underscore the potential of precision medicine strategies that target ferroptosis, epigenetic regulation, and tumor-specific biomarkers, offering new avenues for therapeutic intervention in colorectal cancer patients, particularly those with core-originating tumor regions. Our work exemplifies the broader goal of functional and genomic precision medicine in cancer, aligning distinct mechanistic insights with shared therapeutic objectives. Citation Format: Ji Min Lee. Harnessing epigenetic and metabolic biomarkers for targeted immunotherapy in colorectal cancer: Advances in precision medicine for solid tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B011.