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Recent work has demonstrated that the response of ALM to immune checkpoint blockade is inferior to that of cutaneous melanoma (CM). Here we performed bulk genomic and transcriptomic sequencing of tumor tissue from 28 ALM and 5692 CM cases. Similar to prior studies, ALM was associated with a significantly lower incidence of point mutations, including in the <jats:italic>TERT<\/jats:italic> promoter and <jats:italic>BRAF<\/jats:italic>, but increased numbers of gene amplifications, notably of <jats:italic>CCND1<\/jats:italic>, <jats:italic>HMGA2<\/jats:italic>, and <jats:italic>MDM2<\/jats:italic>. Reactome pathway analysis revealed enhancement of keratinization and PI3K\/AKT signaling pathways. Overall immunogenicity was decreased in ALM, which possessed lower IFN\u03b3 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and T\u2010cell inflammatory (<jats:italic>p<\/jats:italic>\u2009=\u20090.03) pathway scores than CM. Despite higher computationally inferred levels of myeloid dendritic cells (<jats:italic>p<\/jats:italic>\u2009=\u20090.006), neoantigen load independent of predicted HLA binding affinity was lower (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01) in ALM versus CM. Assessment of classical and nonclassical HLA mRNA levels revealed upregulation of HLA\u2010G, suggesting alternative ALM immune evasion pathways in the setting of lower PD\u2010L1 expression (<jats:italic>p<\/jats:italic>\u2009=\u20090.005). Additional research is needed to better understand and therapeutically target signaling networks in the ALM tumor microenvironment.<\/jats:p>","DOI":"10.1111\/pcmr.70027","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T04:44:19Z","timestamp":1747975459000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Comprehensive Profiling of Acral Lentiginous Melanoma Reveals Downregulated Immune Activation Compared to Cutaneous Melanoma"],"prefix":"10.1111","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7789-2049","authenticated-orcid":false,"given":"Stephanie J.","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Medicine University of Southern California Keck School of Medicine  Los Angeles California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Xiu","sequence":"additional","affiliation":[{"name":"Caris 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