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Here, Quiescin Sulfhydryl Oxidase 2 (QSOX2) is identified, a protein involved in disulfide bond formation, is highly expressed in esophageal squamous cell carcinoma (ESCC), and is associated with poor patient prognosis. Functional analyses demonstrated that QSOX2 overexpression markedly potentiated tumor stemness and further promoted chemoresistance, proliferation, and metastasis of ESCC cells. Mechanistically, QSOX2 enhances disulfide bond formation in TSC Complex Subunit 2 (TSC2), stabilizing TSC2\u2010Akt interactions, facilitating phosphorylation of TSC2 at the Ser939 by Akt, and further activating mTOR\/4E\u2010BP1\/c\u2010Myc signaling axis. Intriguingly, cancer\u2010associated fibroblasts\u2010secreted IGF\u20101 upregulates QSOX2 expression via IGF1R\/Akt\/mTOR\/c\u2010Myc pathway, establishing a positive feedback loop that sustains ESCC cell stemness. Targeting QSOX2 with Ebselen, in combination with mTOR inhibitor Rapamycin and chemotherapy, effectively downregulates c\u2010Myc expression and induces tumor dormancy in a mouse xenograft model. Therefore, the findings reveal that QSOX2\u2010mediated disulfide bond modification enhances tumor stemness by activating mTOR signaling, highlighting a promising therapeutic target in ESCC.<\/jats:p>","DOI":"10.1002\/advs.202500597","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T06:11:51Z","timestamp":1748412711000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["QSOX2\u2010Mediated Disulfide Bond Modification Enhances Tumor Stemness and Chemoresistance by Activating TSC2\/mTOR\/c\u2010Myc Feedback Loop in Esophageal Squamous Cell Carcinoma"],"prefix":"10.1002","volume":"12","author":[{"given":"Wo\u2010Ming","family":"Chen","sequence":"first","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Guangdong\u2010Hong Kong Joint Laboratory for RNA Medicine Medical Research Center Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010Sen University  Guangzhou 510120 P. 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