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Through transcriptomic analyses and functional assays, we identified TNIK as a regulator of a MYC-dependent transcriptional network that coordinates epithelial-mesenchymal plasticity and cell proliferation in LUSC. Depletion of TNIK reprogrammed LUSC cells from a hybrid epithelial\/mesenchymal state towards an epithelial, senescent-like state characterized by reduced cell migration, invasion, reduced DNA synthesis, and enhanced \u03b2-galactosidase activity. Using a small-molecule screen approach, we found that TNIK inhibitors cooperated with agents suppressing the histone methyltransferase and MYC binding partner EZH2, which further suppressed partial epithelial-to-mesenchymal transition (pEMT). Mechanistically, we identified MYC as a key downstream TNIK effector in LUSC cells: MYC depletion phenocopied the effects of TNIK loss on pEMT and senescence, and restoring MYC expression bypassed the effects of TNIK depletion. Collectively, these results implicate TNIK in the mechanisms linking epithelial-mesenchymal plasticity with proliferation and evasion of senescence and provide insights into future strategies for the clinical deployment of TNIK inhibitors in LUSC and other TNIK-dependent malignancies.<\/jats:p>","DOI":"10.64898\/2026.08.28.747625","type":"posted-content","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T16:55:17Z","timestamp":1788195317000},"source":"Crossref","is-referenced-by-count":0,"title":["TNIK maintains a MYC-driven partial EMT state that supports proliferation and evasion of senescence in lung squamous cell carcinoma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0431-0677","authenticated-orcid":false,"given":"Mohaddase","family":"Hamidi","sequence":"first","affiliation":[{"name":"Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA"},{"name":"Cancer Signaling and 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