{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:34:41Z","timestamp":1785429281783,"version":"3.56.0"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82160598"],"award-info":[{"award-number":["82160598"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82160598"],"award-info":[{"award-number":["82160598"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"name":"First-Class Discipline Team of Skin & Mucosal Regenerative Medicine of Kunming Medical University","award":["2024XKTDTS01"],"award-info":[{"award-number":["2024XKTDTS01"]}]},{"award":["2024XKTDTS01"],"award-info":[{"award-number":["2024XKTDTS01"]}],"id":[{"id":"https:\/\/ror.org\/038c3w259","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Programs of Yunnan Fundamental Research Project","award":["202301AU070218"],"award-info":[{"award-number":["202301AU070218"]}]},{"name":"Programs of Yunnan Applied Basic Research Project-Kunming Medical University Union Foundation","award":["202301AY070001-165"],"award-info":[{"award-number":["202301AY070001-165"]}]},{"award":["202301AY070001-165"],"award-info":[{"award-number":["202301AY070001-165"]}],"id":[{"id":"https:\/\/ror.org\/038c3w259","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Yunnan Province Caiyun Postdoctoral Support Program Innovation Project"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Chronic microenvironment stress contributes to the progression of melanoma, yet practical tools for quantifying tumor stress adaptation remain limited. Methods: Using disulfiram as a system-level probe, we identified shared regulatory modules between disulfiram-related targets and melanoma-associated genes, which are integrated into pathways regulating apoptosis and hypoxia\/oxidative stress. From these modules, we devised a stress adaptation score (BiScore) based on hallmark gene characteristics and assessed its prognostic significance in melanoma cohorts. Results and Conclusions: In the TCGA-SKCM dataset, a higher binuclear score correlated with poorer overall survival and remained an independent prognostic factor even after adjusting for clinical covariates. This observation was externally validated for distant metastasis-free survival rate in the GSE65904 cohort. Tumors with high binuclear expression consistently exhibited reduced immune infiltration and were weakly associated with mutation load, suggesting that the stress adaptation axis operates independently of gene mutation burden. Single-cell analyses demonstrated that stress-related signals were distributed across both malignant and stress-responsive microenvironmental compartments. In melanoma cell lines, hypoxia induces HIF-1\u03b1 expression and shifts apoptosis-related proteins towards an anti-apoptotic state, and NAC attenuated CoCl2-induced ROS accumulation. In conclusion, these findings establish BiScore as a quantitative framework for capturing stress adaptation states linked to adverse outcomes in melanoma.<\/jats:p>","DOI":"10.3390\/cancers18121897","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:48:35Z","timestamp":1781138915000},"page":"1897","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Hypoxia-Apoptosis Stress-Adaptation State Defines Immune-Low Melanoma and Predicts Metastatic Risk"],"prefix":"10.3390","volume":"18","author":[{"given":"Saige","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China"},{"name":"Key Laboratory of Skin and Mucosal Injury Repair, Regeneration & Active Peptides of Yunnan Provincial Department of Education, Regenerative Medicine Research Center, Faculty of Basic Medical Science, Kunming Medical University, Kunming 650500, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, Kunming 650032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1038\/s41572-025-00603-8","article-title":"Cutaneous melanoma","volume":"11","author":"Tasdogan","year":"2025","journal-title":"Nat. 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