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Purpose: Treatment of metastatic melanoma has dramatically improved in recent years, thanks to the development of immunotherapy and BRAF-MEK–targeted therapies. However, these developments revealed marked heterogeneity in patient response, which is yet to be fully understood. In this work, we aimed to associate the proteomic profiles of metastatic melanoma with the patient clinical information, to identify protein correlates with metastatic location and prior treatments. Experimental Design: We performed mass spectrometry–based proteomic analysis of 185 metastatic melanoma samples and followed with bioinformatics analysis to examine the association of metastatic location, BRAF status, survival, and immunotherapy response with the tumor molecular profiles. Results: Bioinformatics analysis showed a high degree of functional heterogeneity associated with the site of metastasis. Lung metastases presented higher immune-related proteins, and higher mitochondrial-related processes, which were shown previously to be associated with better immunotherapy response. In agreement, epidemiological analysis of data from the National Cancer Database showed improved response to anti-programmed death 1, mainly in patients with lung metastasis. Focus on lung metastases revealed prognostic and molecular heterogeneity and highlighted potential tissue-specific biomarkers. Analysis of the BRAF mutation status and prior treatments with MAPK inhibitors proposed the molecular basis of the effect on immunotherapy response and suggested coordinated combination of immunotherapy and targeted therapy may increase treatment efficacy. Conclusions: Altogether, the proteomic data provided novel molecular determinants of critical clinical features, including the effects of sequential treatments and metastatic locations. These results can be the basis for development of site-specific treatments toward treatment personalization.

Clinical Proteomics of Metastatic Melanoma Reveals Profiles of Organ Specificity and Treatment Resistance