Mucosal exposomes are the internal frontline of defense against xenobiotics, pathogens, and microbiota. The mucosal network of human immunity is closely involved in maintaining whole-body homeostasis and the course of chronic human diseases, including cancer. Colorectal cancer (CRC) is widely considered a chronic disease with many etiologies attributed to environmentally modifiable risk factors, leading to the activation of integrated stress responses (ISR). ISR, as a cellular adaptation pathway, plays a critical role in modulating gut pathological processes via global translational inhibition and upregulation of early stress-responsive signals. Considering chronic stress responses, this chapter addresses the diverse pathological processes of tissue injury, senescence, cellular transformation, and inflammatory distress in the mucosal exposome, all of which play critical roles in modulating tumorigenesis and malignancy. In particular, diet, xenobiotic agents including chemotherapeutics, and gut microbiota are closely associated with the mucosal tumor microenvironment and prognosis in patients with chronic gut inflammation and CRC. Integrated analyses of mucosal complexity and human pathophysiology could provide new insights into systemic processes and interventions against malignant processes in human mucosal exposomes.