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Often diagnosed at advanced stages, MM shows poor responses to conventional therapies, and no standardized treatment regimen currently exists. Progress in preclinical modeling, including cell lines, patient\u2010derived xenografts (PDXs), organoids (PDOs), and comparative animal models\u2014has provided valuable tools for studying MM pathogenesis and therapeutic resistance. Yet these models remain limited in number, heterogeneity, and standardization, restricting their ability to capture MM's molecular diversity and immunosuppressive microenvironment. Beyond physical platforms, emerging virtual strategies\u2014including computational simulations, artificial intelligence\u2013driven multi\u2010omics integration, and in silico clinical trials\u2014offer scalable, cost\u2010effective complements. By simulating tumor\u2013immune\u2013drug interactions using minimal biospecimens, these models offer a unique platform for hypothesis testing and patient stratification in this rare cancer type. This review summarizes MM's clinicopathological features and therapeutic challenges, evaluates current preclinical models, and highlights the synergistic integration of biological and virtual approaches. Future efforts should prioritize MM\u2010specific repositories, multi\u2010model integration, and incorporation of in silico pipelines to accelerate translational research and improve outcomes in this highly lethal malignancy.<\/jats:p>","DOI":"10.1111\/pcmr.70094","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T05:45:31Z","timestamp":1780983931000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical and Virtual Models of Mucosal Melanoma: Bridging Translational Gaps in a Rare and Lethal Cancer"],"prefix":"10.1111","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3894-529X","authenticated-orcid":false,"given":"Xiangjie","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial\u2010Head Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology Shanghai Jiao Tong University School of Medicine  Shanghai 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Shanghai China"},{"name":"Shanghai Key Laboratory of Stomatology &amp; Shanghai Research Institute of Stomatology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial\u2010Head Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology Shanghai Jiao Tong University School of Medicine  Shanghai China"},{"name":"National Center for Stomatology National Clinical Research Center for Oral Diseases  Shanghai China"},{"name":"Shanghai Key Laboratory of Stomatology &amp; Shanghai Research Institute of Stomatology  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoji","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial\u2010Head Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology Shanghai Jiao Tong University School of Medicine  Shanghai 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