HIF-1alpha pathway is a therapeutic vulnerability in mucinous colorectal cancer

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-1alpha (HIF-1alpha)-centered regulatory program as a defining transcriptional hallmark of muCRC.Regulon reconstruction revealed that HIF-1alpha 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-1alpha protein and target gene expression in murine and patient-derived mucinous CRC models compared to non-mucinous counterparts.Functionally, pharmacologic inhibition of HIF-1alpha 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-1alpha inhibition suppressed SPDEF and MUC2 expression, indicating that hypoxia signaling sustains mucinous differentiation and tumorigenic capacity. Collectively, these findings identify HIF-1alpha 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.