Abstract LRRK2-G2019S is the most prevalent variant associated with Parkinson’s disease (PD), found in 1–3% of sporadic and 4–8% of familial PD cases. Intriguingly, emerging clinical studies have suggested that LRRK2 G2019S mutation carriers have an overall increased risk of cancer, including colon cancer. However, it remains to be experimentally tested whether and how this mutant directly affects cancer development. Here, by using the AOM/DSS-induced colitis-associated colon cancer model combined with LRRK2 G2019S knock-in (KI) mice, we found that LRRK2 G2019S promoted the pathogenesis of colon cancer, characterized by increased tumor loads and tumor-promoting cytokines compared with those in wild-type controls. Immunoblotting and immunofluorescence indicated that expression levels of Cyclin-D1, Ki-67, β-catenin and p-STAT3 were dramatically increased in the colon of KI mice, and these proteins are well known to promote the pathogenesis of colon cancer. As inflammation is a major factor contributing to the progression of colon cancer, we thus further tested if LRRK2 G2019S promotes colitis in the initiation of the disease. Indeed, we found KI mice were more susceptible to colitis induction, evident by rapid body weight loss and elevated clinical histology score. Mechanistically, LRRK2 G2019S promoted gut inflammasome activation and enhanced the activation of the NF-ƙB and MAPK pathways upon Dectin-1 stimulation. Together, our data for the first time provide direct evidence that gain-of-function of kinase activity in LRRK2 promotes colon cancer development, implicating LRRK2 as a potential target in colon cancer, especially in those LRRK2 G2019S carrier patients and cancer with hyper LRRK2 expression. Startup fund from the Department of pathology at the University of IOWA, NIH R21AG076895, R01 NS104164