The ubiquitin-proteasome system (UPS) is crucial for sustaining proteostasis, and its dysregulation is associated with cancer advancement and resistance to therapy. While proteasome inhibitors have demonstrated clinical efficacy, a comprehensive understanding of 26S proteasome dynamics across cancer types and tumor microenvironments remains limited. We provide a comprehensive analysis of the 26S proteasome within The Cancer Genome Atlas (TCGA) pan-cancer cohort and various single-cell RNA-seq datasets. We thoroughly assessed the expression of all 26S proteasome subunits at the bulk level and their correlations with tumor mutation burden, microsatellite instability, immunological checkpoint profiles, and patient survival. Network analysis via STRING identified conserved and cancer-specific proteasome interaction modules, elucidating context-dependent regulation mechanisms. To elucidate cellular heterogeneity, we examined single-cell datasets from several tumor types, uncovering unique proteasome expression profiles between malignant and immune cell populations, indicating a possible function in immune regulation. This study provides a comprehensive pan-cancer and single-cell characterization of the 26S proteasome, elucidating its context-specific functions in tumor-immune interactions and identifying potential avenues for therapeutic intervention within the ubiquitin-proteasome system.