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

GSK3β in intestinal epithelium drives fumarate-dependent reprogramming of neutrophils, promoting colorectal cancer progression and immune evasion.

• Why it matters: Understanding how tumor-infiltrating neutrophils (TINs) become immunosuppressive is crucial for developing effective therapies against colorectal cancer, which often resists current treatments.
• What they did: Using mouse models and multiomics profiling, the study reveals that intestinal epithelial GSK3β orchestrates fumarate accumulation and epigenetic changes in TINs, leading to their immunosuppressive T3 phenotype.
• The result: Pharmacological inhibition of GSK3β with tideglusib reduces TIN reprogramming and enhances checkpoint blockade efficacy, offering a promising combined immunotherapy approach for colorectal cancer.