Tumor-Promoting Inflammation in Serrated Colorectal Neoplasia: Immune Ecosystems and Clinical Implications

Serrated colorectal neoplasia represents a biologically distinct route to colorectal cancer that differs from the conventional adenoma-carcinoma sequence in its molecular alterations, epithelial programs, and microenvironmental evolution. Recent studies indicate that tumor-promoting inflammation and dynamic tumor-microenvironment interactions are integral to the evolution of serrated tumors. In this review, we discuss serrated neoplasia as a process shaped by heterogeneous immune ecosystems rather than a uniform inflammatory state. We propose two broad immune trajectories: an inflamed/antigenic trajectory frequently associated with mismatch repair deficiency and microsatellite instability and a stromal-dominant, immune-excluded trajectory more commonly linked to microsatellite stable serrated cancers. We further organize the major proposed mechanistic axes of tumor-promoting inflammation into interconnected processes: epithelial reprogramming, stromal immune exclusion, and persistent inflammatory signaling. Finally, we highlight the potential clinical relevance of immune ecosystem divergence, particularly during the transition from sessile serrated lesions to sessile serrated lesions with dysplasia, and discuss future directions for risk stratification and ecosystem-based intervention in serrated colorectal neoplasia.