Rewiring tumor visibility: The immunopeptidome as a dynamic interface between antigen processing, microenvironmental stress, and immune recognition

The tumor immunopeptidome dictates whether malignant cells remain visible or invisible to immune surveillance, yet its regulation extends far beyond canonical antigen processing. Here, we synthesize recent insights into how proteasomes, immunoproteasomes, transporter associated with antigen processing (TAP), endoplasmic reticulum aminopeptidase (ERAP), and alternative pathways collectively shape peptide presentation, and how tumor-intrinsic rewiring intersects with microenvironmental stressors such as hypoxia, acidity, and epithelial-mesenchymal transition (EMT). We highlight post-translationally modified ligands as a qualitatively distinct class of tumor antigens, expanding the therapeutic landscape. Across various cancers, the immunoproteasome emerges as both a biomarker and a barometer, with prognostic and predictive value contingent upon the immune context. This duality highlights the necessity for context-aware therapeutic strategies, encompassing selective immunoproteasome modulation, TAP2-based biomarkers, and post-translational modification (PTM)-directed vaccines. Framing the immunopeptidome as a dynamic and rewritable interface provides both mechanistic insight into immune escape and a roadmap for precision immuno-oncology.