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However, the mechanisms, biological function, and clinical significance underlying PTM crosstalk are unclear. Here, we performed systematic analyses of 2\u2010hydroxyisobutyrylation (Khib), phosphoproteomic, proteomic, and transcriptomic profiles from 60 esophageal squamous cell carcinoma (ESCC) samples, comprising matched normal, primary tumor, and metastatic lymph node tissues. The integrative analysis identified 4499 proteins co\u2010modified by Khib and phosphorylation on distinct residues. Interestingly, while the two PTMs target distinct motifs across proteins, they engage common motifs within individual proteins. Functionally, Khib and phosphorylation show prevalent positive crosstalk linked to metastatic progression. Mechanistically, Khib mediates this intra\u2010protein crosstalk by recruiting kinases and potentiating phosphorylation events. Machine learning\u2010based artificial intelligence (AI) analysis of secreted proteins with PTM crosstalk revealed an independent and highly effective plasma signature predicting lymph node metastasis. Moreover, molecular subtyping stratified ESCC into three groups, with immunotherapy\u2010resistant Subtype 3 associated with the worst survival. While combined treatment of integrin inhibitor cilengitide and immunotherapy exhibited targeted efficacy. By deciphering the mechanistic basis of Khib\u2010phosphorylation crosstalk, identifying a novel plasma biomarker for lymph node metastasis, and providing a therapeutic strategy to sensitize tumors to immunotherapy, this work collectively advances the precision diagnosis and treatment of ESCC.<\/jats:p>","DOI":"10.1002\/mco2.70815","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:23:49Z","timestamp":1781861029000},"source":"Crossref","is-referenced-by-count":0,"title":["2\u2010Hydroxyisobutyrylation and Phosphorylation Crosstalk Guides Metastasis Prediction and Immunotherapy in Esophageal Squamous Cell Carcinoma"],"prefix":"10.1002","volume":"7","author":[{"given":"Junyi","family":"Li","sequence":"first","affiliation":[{"name":"The Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, China; State Key Laboratory of Metabolic Dysregulation and Prevention and Treatment of Esophageal Cancer School of Convergence Medicine Zhengzhou 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