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This narrative review establishes the biological relevance and evaluates the clinical maturity of mass spectrometry\u2010based proteomics, with particular emphasis on spatially resolved approaches, as a powerful strategy to address this critical diagnostic gap. We position spatial proteomics within the broader landscape of DNA\u2010, RNA\u2010, and protein\u2010based molecular diagnostics for functional manifestation, highlighting that genomic and transcriptomic methods offer standardized, higher\u2010throughput workflows but limited insight into the tumor microenvironment and functional protein\u2010level biology. Laser capture microdissection\u2013mass spectrometry, imaging mass spectrometry, and Deep Visual Proteomics each preserve spatial and single\u2010cell resolution. However, protein expression is inherently plastic, shaped by microenvironment, tissue handling, and technical artifact, and no existing study has been powered specifically for the diagnostically indeterminate categories where clinical need is greatest. We discuss how compartment\u2010resolved \u201cmitochondrial\u2010high\u201d profiles and \u201cimmune\u2010low\u201d microenvironment states, evidence largely extrapolated from progression and metastatic biology, might inform future risk stratification. Spatial proteomics represents a biologically promising, but not yet clinically validated, extension of morphology\u2010led melanoma diagnosis, with the potential to resolve functional states within annotated tumor compartments. Integrated with AI\u2010guided tissue annotation, compartment\u2010resolved mass spectrometry and spatial proteomic profiling could, following prospective validation, help improve the distinction between borderline melanocytic lesions and melanoma while refining patient risk stratification.<\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/ijd70665-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3601-3893","authenticated-orcid":false,"given":"Jeovanis","family":"Gil","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine Lund University  Lund Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7140-8925","authenticated-orcid":false,"given":"Gy\u00f6rgy","family":"Marko\u2010Varga","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine Lund University  Lund Sweden"},{"name":"Department of Biotechnology College of Life Science and Biotechnology, Yonsei University  Seoul Korea"},{"name":"1st Department of Surgery Tokyo Medical University  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,29]]},"reference":[{"key":"e_1_2_11_2_1","unstructured":"American Cancer Society Melanoma Skin Cancer: Key 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