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Solid pseudopapillary neoplasm (SPN) of the pancreas is a rare but distinct disease that remains poorly understood, especially at proteome level. We report comprehensive mass spectrometry-based proteomic analyses of SPN (n = 13) and characterize differences from other pancreatic neoplasms, pancreatic ductal adenocarcinoma (n = 11) and neuroendocrine tumor (n = 10). We discovered that the SPN proteome is uniquely distinct from that of other pancreatic neoplasms. Lysosome-related proteins are enriched and upstream lysosomal processes transcriptional regulators, MITF and TFE3, are overexpressed in SPN. MITF protein expression is more specific for SPN than TFE3, previously considered the most specific immunohistochemical marker. Since lysosomal-related processes are connected to biological energy generation processes, we profiled metabolic pathways and found that SPN is characterized by higher fatty acid oxidation and lower glycolysis than PDAC and high proteasome pathway activity with many proteasomal proteins upregulated, suggesting a possible link to metabolic adaptation mechanisms in low-nutrient environments. Proteomics characterizes SPN as an immune-cold tumor with low MHC class I expression. Proteome-based receptor tyrosine kinase (RTK) pathway profiling suggests PDGFRA and ERBB2 (HER2) as potential candidates for targeted therapy. Our results provide unique proteomic contribution to the understanding of SPN biology and highlight differences from other pancreatic tumors.