In this study, we aimed to unravel the molecular underpinnings of pleomorphic dermal sarcomas (PDS), rare skin tumors often seen in sun-exposed regions. Using mass spectrometry, we examined proteomic profiles of 20 samples of normal healthy skin tissue (SNT), 27 malignant melanomas (MM), 20 cutaneous squamous cell carcinomas (cSCC), and 24 PDS. Our analysis aimed to: I.) Determine the potential cell of origin for PDS by correlating protein abundance to tumor purity using both RNA- and DNA-sequencing data. II.) Investigate receptor/ligand (R/L) interactions and their related pathways, highlighting distinct signaling differences between cSCC, MM, and PDS. III.) Identify differential protein markers, such as MAP1B_HUMAN, that can distinguish between cSCC, MM, and PDS. IV.) Explore proteins linked to immunosuppression in PDS, with a focus on those related to the negative regulation of interferon-gamma signaling. Together, this comprehensive proteomic exploration provides valuable insights into PDS and potential therapeutic targets.