The Antigen-Presentation Bottleneck in Pediatric Solid Tumors: Developmental Antigens, MHC-I Suppression, and Therapeutic Restoration of Tumor Immune Recognition

Background: Pediatric solid tumors respond poorly to T-cell-directed immunotherapy despite expressing developmentally restricted, cancer-testis, fusion-derived, and lineage-associated antigens, suggesting that therapeutic failure may reflect defective conversion of intracellular antigen expression into surface peptide–major histocompatibility complex class I (pMHC-I) display. This review examines the antigen-presentation bottleneck as a framework for tumor immune invisibility and therapeutic resistance. Methods: We conducted a narrative mechanistic synthesis of pediatric and translational evidence on antigen repertoires, MHC-I and antigen-processing machinery dysfunction, mechanisms of presentation loss, therapeutic restoration, pMHC-directed immunotherapy, and MHC-independent bypass strategies. Results: Antigen expression does not reliably predict natural presentation. Presentation failure may result from HLA loss, coordinated transcriptional repression, developmental and epigenetic states, altered trafficking, SUMOylation, and autophagy-mediated MHC-I degradation. Potentially reversible defects can be targeted through cytokine signaling, NF-κB/IRF1/NLRC5 reactivation, epigenetic or lineage reprogramming, and inhibition of post-translational MHC-I loss; irreversible defects favor MHC-independent surface targeting. Conclusions: Pediatric solid tumors may be antigen-invisible rather than antigen-poor. Therapeutic matching should assess antigen abundance, HLA integrity, antigen-processing competence, natural peptide presentation, quantitative pMHC density, and spatial and longitudinal heterogeneity, then restore presentation or deliberately bypass it. The framework distinguishes the presentation phenotype (quantitative pMHC insufficiency versus qualitative loss or functional absence of a required HLA/APM element) from the underlying mechanism (soft/potentially reversible versus hard/structural) because these dimensions have different biomarker and therapeutic implications.