Immune microenvironment evolution across the serrated neoplasia pathway and its relevance to immunotherapy.

The serrated neoplasia pathway is a major molecular route to colorectal carcinogenesis, accounting for approximately 15%-30% of sporadic colorectal cancers and characterized by early BRAF V600E mutation, CpG island methylator phenotype, and distinct histopathologic features. Although immune checkpoint inhibitors have shown clear efficacy in MSI-H/dMMR colorectal cancer, serrated pathway-associated tumors remain highly heterogeneous in their molecular evolution and immune microenvironments. This heterogeneity may be associated with diverse immune phenotypes and potentially variable responsiveness to immunotherapy. Emerging evidence suggests that changes in the immune microenvironment may begin before invasive transformation.

In sessile serrated lesions, early immune surveillance features, including intraepithelial CD8+ tissue-resident memory T cells, may be detectable before the development of a high tumor mutational burden state, whereas immune checkpoint upregulation and enrichment of regulatory immune populations indicate that adaptive immunosuppressive programs may arise in parallel. In this review, we synthesize evidence that immune alterations in serrated lesions are not merely accompanying features, but part of the biologic context in which lesions progress and later diverge. We therefore propose a stage-linked, hypothesis-generating framework in which early serrated lesions enter an immune-engaged yet counter-regulated state before later tending toward predominant inflamed MSI-H-like or immune-excluded MSS-like immune niches. Linking serrated lesions to changes in the immune microenvironment matters because it provides a biologic explanation for why morphologically similar precursor lesions may not be progression-equivalent and why advanced serrated-pathway cancers may diverge toward inflamed MSI-H-like or immune-excluded MSS-like states.

Although not yet sufficient to alter classification or treatment selection, this perspective defines specific priorities for biomarker development, risk stratification, and mechanism-based therapeutic testing.