Intestinal epithelial GSK3β governs fumarate-dependent neutrophil reprogramming to promote colorectal cancer.

Tumor-infiltrating neutrophils (TINs) promote colorectal cancer progression and therapeutic resistance, but their reprogramming mechanisms remain unclear. Using mouse models and multiomics profiling, we reveal that intestinal epithelial glycogen synthase kinase-3-β (GSK3β) orchestrates fumarate-dependent TIN polarization. GSK3β-primed T3 neutrophils express FTH1 and PD-L1, conferring ferroptosis resistance and immune evasion. Mechanistically, nuclear GSK3β phosphorylates linker histone H1FX, triggering its proteasomal degradation via USP43 dissociation and elevating chromatin accessibility for glycolytic gene transcription. Lactate inactivates fumarate hydratase through lactylation, driving intratumoral fumarate accumulation. Fumarate inhibits KDM2B activity in TINs, elevating histone H3 lysine 36 dimethylation to trigger epigenetic reprogramming toward immunosuppressive T3 neutrophils. Pharmacological GSK3β inhibition with tideglusib attenuates T3 polarization and potentiates checkpoint blockade in preclinical colorectal cancer models. Our work establishes a metabolic-epigenetic axis controlling TIN reprogramming and suggests combinatorial immunotherapies for CRC.