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The identified genes were validated in independent meta cohorts from GEO, followed by transcriptome-wide association study (TWAS) validation using Genotype-Tissue Expression (GTEx) and UK Biobank datasets. Additionally, we analyzed machine learning-driven signature (CMLS) development, tumor microenvironment characteristics, immunotherapy response, and potential therapeutic targets. Finally, single-cell and spatial transcriptomics provided further biological insights and the pathomechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>\n                      Our study identified two distinct molecular subtypes of SKCM using multimodal data integration with the MOVICS package: Cancer Subtype 1 (CS1) and CS2. CS2 showed a better prognosis and was enriched in immune-suppressive pathways such as WNT\u2013\u03b2 signaling, while CS1 exhibited higher activation of the PI3K pathway and DNA repair mechanisms, along with greater tumor invasiveness. TWAS analysis results combined the findings from TCGA-SKCM and the meta-cohort, identifying six significant prognostic-related genes (SPRGs). The CMLS prognostic model, based on SPRGs (\n                      <jats:italic>CAP2<\/jats:italic>\n                      ,\n                      <jats:italic>SELL<\/jats:italic>\n                      ,\n                      <jats:italic>and LAPTM5<\/jats:italic>\n                      as risk factors and\n                      <jats:italic>GZMA<\/jats:italic>\n                      ,\n                      <jats:italic>FCER1G<\/jats:italic>\n                      , and\n                      <jats:italic>LYZ<\/jats:italic>\n                      as protective factors), stratified patients into high-group (poorer survival) and low-risk groups. Single-cell and spatial transcriptomic analyses further validated CMLS prognostic results, highlighting distinct tumor microenvironment interactions and progression trajectories.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Identifications of molecular subtypes and CMLS represent a valuable tool for early prediction of patient prognosis and for screening potential candidates likely to benefit from immunotherapy, with broad implications for clinical practice foundation for personalized therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40246-026-00919-w","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T22:03:11Z","timestamp":1773698591000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A cross-scale multimodal framework identifies clinically actionable immunotherapy biomarkers in melanoma through bulk to single-cell and spatial transcriptomics integration"],"prefix":"10.1186","volume":"20","author":[{"given":"Wuda","family":"Huoshen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junkai","family":"Xiong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilong","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjie","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changqing","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"issue":"10400","key":"919_CR1","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/S0140-6736(23)00821-8","volume":"402","author":"GV Long","year":"2023","unstructured":"Long GV, Swetter SM, Menzies AM, Gershenwald JE, Scolyer RA. 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