MINI REVIEW article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
This article is part of the Research TopicExploring immune low-response states through single-cell technologies and spatial transcriptomicsView all 32 articles
Epigenetic Control of Antigen Presentation Failure in Osteosarcoma: From Single-Cell Chromatin Maps to Therapeutic Strategies
Provisionally accepted
Yan He
Heng Wu*- Department of Spinal Surgery,Affiliated Sports Hospital of Chengdu Sport University, Chengdu, China
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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.
Keywords: Osteosarcoma, Antigen Presentation, DNA Methylation, Immune Evasion, Single-cell ATAC-seq, interferon signaling
Received: 19 Oct 2025; Accepted: 17 Nov 2025.
Copyright: © 2025 He and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Heng Wu, 2907928925@qq.com
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