Malignant melanoma is the fifth most common malignancy diagnosed in both women and men, and its incidence is on the rise, particularly in the immunosuppressed population, including patients living with HIV (PLWH). The increased survival of HIV+ patients has been paralleled by an increased risk of developing a variety of non-AIDS-related malignancies, including melanoma. Indeed, melanoma appears to be 2.6 times more common in patient with HIV/AIDS than in the general population, and its behavior is frequently more aggressive in these patients. Immune checkpoint inhibitors and targeted therapy for BRAF/MEK oncoproteins are standard of care for patients with melanoma. Data on the role of these therapeutic regimens in PLWH are limited and these patients are frequently excluded from clinical trials testing novel drugs and combinations. In order to better use these novel therapies in this population, a deeper understanding of their tumor and tumor microenvironment is essential to ultimately implement predictive biomarkers for inclusion to clinical trials and to discover novel targets for therapy. Prior knowledge of the molecular basis of malignant melanoma, in general, has been based on genetic analysis and expression profiles in bulk tissue samples and, more recently, on single-cell technologies. These data are missing the spatial organization of the tumor, a key element traditionally used by pathologists for nosological interpretation, and now accessible through spatial genomics and transcriptomics. Analysis of this dimension may offer an high-content overview of tumor heterogeneity, and ultimately better understand the spatial localization and co-localization of potential biomarkers and drug targets. Our hypothesis is that there are differences in the tumor and its microenvironment in melanoma from patients with HIV/AIDS compared with patients without, and we can gain a deeper molecular knowledge of these differences by the use of spatial transcriptomics. To this end, we propose to explore the following: Specific Aim 1. Study a targeted (cancerrelated and its microenvironment) spatial transcriptome profile of melanoma in PLWH compared with non-HIV patients, to determine biomarkers to select patients that can benefit from current therapies and to discover novel targets to expand therapeutic options. Specific Aim 2. Study the progression from precursor lesions (dysplastic nevi) to melanoma, and from melanoma to metastatic melanoma with the use of spatial transcriptomics in HIV/AIDS patients’ samples compared to melanoma samples from non-HIV/AIDS patients. These studies will help to recognize molecular pattern in HIV/AIDSrelated melanomas, and we can leverage this knowledge for better patient stratification and intervention.