Gut microbiota and macrophage crosstalk: implications for colitis-associated colorectal cancer

Colitis-associated colorectal cancer (CAC) is one of the most severe complications associated with inflammatory bowel disease (IBD). Within the global landscape of cancer epidemiology, colorectal cancer (CRC) ranks among the leading malignancies in terms of both incidence and mortality. CAC, which arises in the context of IBD-including Crohn's disease and ulcerative colitis-represents a distinct subtype of CRC that is closely linked to chronic intestinal inflammation. The pathogenesis of CAC is driven by the complex intestinal microenvironment, characterized by dynamic interactions among immune cells, epithelial cells, and the gut microbiota. In this setting, macrophages serve as central regulators of intestinal immunity and exhibit significant plasticity in response to microbial stimuli. Under homeostatic conditions, macrophages contribute to tissue integrity through phagocytic activity and the production of anti-inflammatory mediators. However, during prolonged inflammation, persistent exposure to a dysbiotic microbiota induces functional reprogramming of macrophages toward a pro-tumorigenic phenotype. Pathogenic bacteria enriched in CAC tissues-such as Fusobacterium nucleatum and Escherichia coli-secrete virulence factors that promote macrophage polarization into an immunosuppressive M2-like state, thereby facilitating the establishment of a tumor-permissive microenvironment. In contrast, beneficial bacterial genera such as Bifidobacterium and Lactobacillus are frequently depleted in CAC, compromising the capacity of macrophages to mediate anti-inflammatory and immunoregulatory responses and further accelerating disease progression. This article reviews the intricate bidirectional interactions between the gut microbiota and macrophages, and emphasizes the molecular mechanisms by which gut microbes influence macrophage polarization and function, as well as how the phenotypic changes of macrophages shape the tumor microenvironment to promote the development of CAC. Additionally, the article explores potential therapeutic strategies aimed at inhibiting the inflammation-to-cancer transition by targeting these interactions.