<p>Cronkhite–Canada syndrome (CCS) is a rare non-inherited hamartomatous polyposis syndrome with unknown pathogenesis. To investigate this, we performed single-cell RNA sequencing, spatial in situ sequencing, and bulk RNA-seq on colon biopsies from CCS patients and healthy controls, along with cytokine profiling and organoid/cell line experiments. Multi-omics analysis revealed goblet cell hyperplasia and increased mucin secretion, spatially associated with an inflammatory niche consisting of TNF⁺ Th1 cells, FCN1⁺ monocytes, and IL1B⁺ macrophages, all highly active in CCS. Functional assays showed that low-dose TNF-α drives monocyte differentiation into IL-1β-secreting macrophages, while IL-1β induces epithelial PGE₂ production, which further amplifies IL-1β secretion, establishing a self-reinforcing loop. An independent cohort confirmed mild elevation of peripheral TNF-α and TNF/IL-1 pathway activation. These findings delineate a pathogenic circuit linking adaptive immune dysregulation, innate remodeling, and epithelial changes, positioning the TNF-α/IL-1β/PGE₂ axis as the driver of mucus accumulation and hamartoma formation, offering new potential therapies for CCS.</p> Graphical Abstract <p>Key features distinguishing Cronkhite–Canada syndrome (CCS) hamartomatous polyps from healthy intestinal tissues and crosstalk among CD4⁺ T-helper 1 TNF⁺ cells, FCN1⁺ monocytes, IL1B⁺ macrophages, and altered epithelial lineage establish a unique immune microenvironment in CCS. This interaction network drives the accumulation of mucus and remodeling of epithelial lineages via paracrine signaling (e.g., TNF-α/IL-1β/PGE₂ axis), collectively forming a pathogenic triad that underpins the development of CCS lesions.</p> <p></p>