<p>Colon adenocarcinoma (COAD), the most common subtype of colon cancer, often arises from adenomas. However, the mechanisms driving the adenoma-to-adenocarcinoma transition remain unclear, hindering early intervention and treatment. Single-cell RNA sequencing revealed that CD8⁺ exhausted T cells (Tex) were significantly enriched in adenoma and carcinoma tissues compared to adjacent normal tissues. Pseudotime analysis and cell-cell communication analysis together revealed a close association between CD8⁺ Tex cells and epithelial cells (EPCs) during the adenoma-to-adenocarcinoma transition. Ligand-target gene interaction and clustering analysis identified the most critical gene set influenced by CD8⁺ Tex in the adenoma-to-adenocarcinoma transition. Among these, runt-related transcription factor 2 (RUNX2) was validated as a critical risk factor through the nine-gene risk score model, TCGA data, and qRT-PCR, demonstrating its role in driving this transition. The RUNX2-specific inhibitor CADD522 suppressed RUNX2 expression in vitro and inhibited the adenoma-to-adenocarcinoma transition in the AOM/DSS model. RUNX2 overexpression promoted proliferation, invasion, migration, and adenoma-to-adenocarcinoma transition-related markers in HCT116 and HCT15 cells, while its knockdown reversed these effects. The tumor necrosis factor receptor superfamily member 1 A (TNFRSF1A) agonist tumor necrosis factor-alpha (TNF-α) upregulated RUNX2 expression and partially mitigated the effects of RUNX2 knockdown. Conversely, TNFRSF1A inhibitor Atrosab downregulated RUNX2 expression and partially reversed RUNX2 overexpression-induced adenoma-to-adenocarcinoma transition. Multiplex immunofluorescence confirmed a close spatial association between CD8⁺PD-1⁺ Tex cells and RUNX2⁺ EPCs. In summary, CD8⁺ Tex cells may activate RUNX2 in malignant EPCs through TNF-α binding to TNFRSF1A, promoting the adenoma-to-carcinoma transition and contributing to poor prognosis.</p>