Role of the Proteasome System in Shaping Cellular Immunological Characteristics and Its Impact in Modulating the Pathogenesis of Immune-Related Diseases

Background: The 26S proteasome degradation system is a central regulator of protein homeostasis and immune function, integrating antigen processing, inflammatory signaling, and cell fate decisions. Dysregulation of this system has profound consequences for immune tolerance, immune evasion, and immune-mediated pathology. Summary: In this review, we examine the roles of the constitutive 26S proteasome and the inducible immunoproteasome in shaping cellular immunological characteristics, with a particular focus on mesenchymal stem cells and cancer cells, two cell types that exhibit context-dependent immune privilege. We discuss how proteasome dynamics regulate antigen presentation, cytokine production, and the expression of immune checkpoint and immunomodulatory molecules under physiological and stress conditions such as hypoxia and metabolic imbalance. We also summarize evidence linking altered proteasome function to the pathogenesis of autoimmune, immunodeficiency, and autoinflammatory diseases. Key Messages: The proteasome system is a pivotal molecular hub controlling immune visibility and immune escape. Understanding how distinct proteasome isoforms operate in different microenvironments will be essential for developing targeted immunomodulatory and proteasome-based therapeutic strategies.