PSME2 (proteasome activator subunit 2) functions as a regulatory component of the PA28 immunoproteasome complex, enhancing the generation of MHC class I-binding peptides by altering proteasomal cleavage patterns 1. This modification is critical for efficient antigen processing and presentation to cytotoxic T lymphocytes. Mechanistically, PSME2 operates through multiple interconnected pathways. It promotes association of PA28α/β with immunoproteasomes to expand the antigenic peptidome 1, while also regulating autophagy through IL-6/STAT3 signaling in certain cancers 2. Additionally, PSME2 inhibits BNIP3-mediated autophagy in renal cell carcinoma 3. In disease contexts, dysregulated PSME2 expression appears context-dependent. Elevated PSME2 promotes malignant progression in esophageal squamous cell carcinoma and osteosarcoma through suppressed autophagy 2, 4, whereas low pre-treatment PSME2 expression predicts favorable response to neoadjuvant chemoimmunotherapy in NSCLC 5. PSME2 serves as a pan-cancer biomarker of M1 macrophage infiltration, correlating with DNA repair and genomic stability 4, and participates in immune responses in ulcerative colitis and kidney transplant rejection 6, 7. Clinically, PSME2 represents a promising therapeutic target. Selective immunoproteasome activators enhancing PSME2 function augment T-cell anti-myeloma activity 1, while PSME2 inhibition combined with STAT3 blockade suppresses tumor growth 2.