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However, the mechanisms driving the adenoma-to-adenocarcinoma transition remain unclear, hindering early intervention and treatment. Single-cell RNA sequencing revealed that CD8\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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\u2009A (TNFRSF1A) agonist tumor necrosis factor-alpha (TNF-\u03b1) 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\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    Tex cells and RUNX2\n                    <jats:sup>+<\/jats:sup>\n                    EPCs. In summary, CD8\n                    <jats:sup>+<\/jats:sup>\n                    Tex cells may activate RUNX2 in malignant EPCs through TNF-\u03b1 binding to TNFRSF1A, promoting the adenoma-to-carcinoma transition and contributing to poor prognosis.\n                  <\/jats:p>","DOI":"10.1038\/s41419-026-08801-2","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T18:08:21Z","timestamp":1777486101000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["RUNX2 drives adenoma-to-carcinoma transition in colon cancer"],"prefix":"10.1038","volume":"17","author":[{"given":"Jin","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyu","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhouyue","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junhao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhui","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieya","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzi","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Ling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxuan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1782-5258","authenticated-orcid":false,"given":"Huiying","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1854-8432","authenticated-orcid":false,"given":"Yingchao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,29]]},"reference":[{"key":"8801_CR1","first-page":"7","volume":"71","author":"RL Siegel","year":"2021","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. 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