Colon cancer (CC) exhibits substantial heterogeneity between right-sided colon cancer (RCC) and left-sided colon cancer (LCC) in terms of embryological origin, molecular characteristics, immune microenvironment, and therapeutic response. Increasing evidence suggests that spatial heterogeneity of the gut microbiota may contribute to these site-specific differences through interactions with local immune, inflammatory, and metabolic microenvironments. Recent studies have also indicated that gut mic