Macrophage-derived WNT regulates tumor immune microenvironment to reduce colitis-associated colon cancer

Prolonged colonic inflammation and ulcerative colitis lead to colon cancer. The rapid growth and treatment-resistant nature of these tumors are primarily influenced by an immunosuppressive tumor microenvironment, which is led by tumor-associated macrophages (TAMs). However, factors influencing or regulating the immunosuppressive nature of TAMs have not been sufficiently studied. In this manuscript, we use a mouse model of colitis-associated colorectal cancer (CRC) to demonstrate that WNT expression in TAMs regulates their immunosuppressive function by inhibiting Glycogen synthase kinase-3 beta (GSK-3β) within the macrophages, possibly through an autofeedback loop. GSK3β is a positive regulator of PD-1 and PD-L1 expression in macrophages and promotes an immunosuppressive microenvironment. Therefore, GSK-3β inhibition alters the immunosuppressive nature of the immune microenvironment and effectively controls tumor growth. In Csf1r.iCre; Porcn^fl/fl mice, the absence of macrophage-derived WNT promotes tumor growth in the model of colitis-associated colon cancer. Absence of macrophage-derived WNT stabilizes GSK-3β in macrophages and promotes an immunosuppressive tumor microenvironment. We also show that pharmacological inhibition of GSK-3β in a macrophage-specific manner, achieved by systemic delivery of a lipo-GSK3β inhibitor, effectively inhibits tumor growth. Therefore, this manuscript demonstrates for the first time that the macrophage-specific modulation of GSK3β can be a potential target to treat colitis-associated colon cancer.