AUTHOR=He Yan , Wu Heng 

TITLE=Epigenetic control of antigen presentation failure in osteosarcoma: from single-cell chromatin maps to therapeutic strategies

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1728091

DOI=10.3389/fimmu.2025.1728091

ISSN=1664-3224

ABSTRACT=Osteosarcoma arises within heterogeneous tumor–immune ecosystems in which impaired antigen visibility—shaped by chromatin programs—limits immune surveillance and blunts responses to immunotherapy. Beyond structural defects in the antigen-processing pathway, Polycomb-mediated repression, DNA hypermethylation, and state-specific enhancer closure converge on the HLA class I/NLRC5/interferon axis to diminish peptide display. These constraints are context dependent, varying across malignant clones, differentiation states, and myeloid and T-cell niches. Traditional bulk assays obscure this complexity; single-cell ATAC-seq, integrated with single-cell and spatial transcriptomics, now resolves promoter–enhancer accessibility at HLA, NLRC5, and antigen-processing genes, distinguishes reversible repression from fixed lesions, and links microenvironmental stress to interferon competence. Translationally, epigenetic reprogramming—targeting Polycomb repressive complex 2 (PRC2), DNA methyltransferases (DNMTs), and complementary regulators (for example, LSD1, BET, CDK4/6, YAP/TEAD)—offers biomarker-guided avenues to restore antigen presentation, provided ecosystem-aware pharmacodynamic readouts track chromatin opening and antigen-presentation recovery across compartments. Despite encouraging preclinical evidence, efficacy will depend on clone selection, scheduling that preserves interferon signaling, and rational combinations with innate agonists and checkpoint blockade. This mini-review synthesizes epigenetic mechanisms of antigen-presentation failure in osteosarcoma and outlines how single-cell chromatin profiling can guide strategies to reinstate tumor antigen visibility.