Abstract 7297: HIF-1α pathway is a therapeutic vulnerability in mucinous colorectal cancer

Abstract Mucinous colorectal cancer (muCRC) represents an aggressive and histologically distinct subtype of CRC characterized by abundant extracellular mucin, right-sided predominance, and poor therapeutic response. Despite its clinical relevance, muCRC-specific therapeutic options are not available.Through comparative single-cell transcriptomic profiling of over 360,000 cells from muCRC and non-muCRC tumors, we identified a hypoxia-inducible factor-1α (HIF-1α)-centered regulatory program as a defining transcriptional hallmark of muCRC.Regulon reconstruction revealed that HIF-1α activity coincides with SPDEF- and TFF3-driven mucinous lineage programs, linking hypoxia signaling to secretory differentiation. Immunohistochemical and spatial transcriptomic analyses confirmed marked elevation of HIF-1α protein and target gene expression in murine and patient-derived mucinous CRC models compared to non-mucinous counterparts.Functionally, pharmacologic inhibition of HIF-1α using PX-478 completely prevented mucinous tumor formation in the genetically engineered mouse models, restoring normal crypt architecture and markedly extending survival. Likewise, PX-478 treatment abolished mucin accumulation and tumor growth in cecum orthotopic patient-derived organoid xenografts. Mechanistically, HIF-1α inhibition suppressed SPDEF and MUC2 expression, indicating that hypoxia signaling sustains mucinous differentiation and tumorigenic capacity. Collectively, these findings identify HIF-1α as a molecular dependency and therapeutic vulnerability in muCRC. Together, these results provide a strong translational rationale for HIF-targeted therapy in mucinous and related serrated CRC subtypes. Citation Format: Yoojeong Seo, Jinho Jang, Kyung-Pil Ko, Jie Zhang, Sohee Jun, Jae-Il Park. HIF-1α pathway is a therapeutic vulnerability in mucinous colorectal cancer [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 7297.