PSMB9 (proteasome 20S subunit beta 9) is an immunoproteasome-specific catalytic subunit that functions as a key component of the proteasome's antigen processing machinery. As part of the 20S proteasome core complex, PSMB9 replaces the constitutive PSMB6 subunit to increase the immunoproteasome's capacity to cleave peptides after hydrophobic and basic residues, thereby generating class I major histocompatibility complex-binding peptides essential for CD8+ T cell activation 1. Mechanistically, PSMB9 expression is upregulated in response to mitochondrial dysfunction through an EEF1A2-dependent pathway, constituting a cellular defense mechanism to preserve proteostasis under stress 2. PSMB9 transcription can be induced via the NONO/PSMB9/ZEB1 signaling axis, which regulates vascular adhesion molecule expression 3. Clinically, PSMB9 variants associate with multiple immune-mediated diseases, including alopecia areata 4. In cancer contexts, PSMB9 demonstrates tumor-suppressive functions: it enhances CD8+ T cell infiltration and cytotoxic marker expression in triple-negative breast cancer 5 and acts as a favorable prognostic marker in melanoma, correlating with immunotherapy response and IFN-γ sensitivity 1. PSMB9 upregulation in natural killer cells associates with slower multiple myeloma progression 6. Mutations in PSMB9 underlie proteasome-associated autoinflammatory syndromes, highlighting its role in immune homeostasis.