ABSTRACT Innate immune sensors and inflammasomes drive an immune response, primarily providing protection against microbial infections and mediating control over sterile insults. However, aberrant innate immune signaling is associated with the pathogenesis of several inflammatory and metabolic diseases, neurodegeneration, and cancer. In the United States, colorectal cancer is the second most common cause of cancer deaths. Innate immunity is a major player in the colon, and thus understanding how innate immune pathways contribute to the various stages of tumor development will be key to improving cancer treatment strategies. We have an extensive track record of discoveries related to innate immune sensors and their role in colitis-associated colorectal cancer. We now seek to continue and expand this research program. The primary focus of this application is to unravel the key mechanisms of novel innate immune sensors and inflammasome regulators discovered in our lab recently and their crosstalk with cell death regulators in the development of colorectal cancer. Basic science supporting this area of research is critical to understanding the fundamentals of innate immune responses. This understanding lays the foundation to explain how defects in these sensing systems lead to the development of disease in humans. Moreover, as the molecules we are studying are central drug targets, our studies will be translated into the development of new therapeutics to treat several devastating diseases.