Sulconazole Suppresses Colorectal Cancer Immune Evasion by Inhibiting Glycolysis to Upregulate OVOL2 PARylation and Induce PANoptosis

Colorectal cancer (CRC) progression involves metabolic reprogramming and immune evasion, but the link between glycolysis-driven epigenetics and immune checkpoints is unclear. OVOL2 is a tumor suppressor, yet its role in metabolic-immune crosstalk is unknown. In CRC cells and mouse models, we studied how OVOL2 loss enhances glycolysis and immune evasion. Multi-omics, CRISPR-Cas9, and pharmacological inhibition dissected the OVOL2-glycolysis-PD-L1 axis. Histone lactylation was assessed via immunoblotting and mutagenesis; OVOL2 PARylation by co-IP and PARP assays. Sulconazole's effects were tested in vitro/in vivo, with immune profiling by flow cytometry and multiplex IHC. OVOL2 deficiency increased glycolysis, lactate, and histone lactylation at the CD274 promoter, upregulating PD-L1 and promoting CD8+ T-cell exhaustion. Sulconazole inhibited glycolysis, reduced lactylation and PD-L1, and restored PARP1-mediated OVOL2 PARylation, inducing ASC-dependent PANoptosis. In mice, sulconazole suppressed tumor growth and metastasis. OVOL2 regulates metabolic-immune crosstalk in CRC. Sulconazole blocks glycolysis-driven PD-L1 expression and restores OVOL2 function, inducing PANoptosis and reversing immune evasion. Repurposing sulconazole offers a promising strategy for glycolytic, immunosuppressive CRC.