Epigenetic Mechanisms of Cancer Immunotherapy Response and Resistance

Immunotherapy, particularly immune checkpoint blockade, has transformed the oncological landscape. However, primary and acquired resistance remains a major clinical challenge, with the majority of patients failing to achieve durable responses. Accumulating evidence indicates that epigenetic alterations in both tumor cells and the surrounding tumor microenvironment (TME) play a key role in orchestrating these resistance phenotypes.Epigenetic mechanisms, including DNA methylation, histone post-translational modifications, chromatin remodeling, non-coding RNA networks, and epitranscriptomic modifications, regulate the expression of immune checkpoints, antigen presentation machinery, and cytokine signaling pathways. Furthermore, epigenetic states govern the differentiation, activation, and exhaustion of tumor-infiltrating immune cells. Understanding this epigenetic rewiring is critical for identifying predictive biomarkers and developing rational combination therapies that pair epigenetic modifiers with immunotherapies.This Research Topic aims to compile original research, reviews, and methodological advances that elucidate how epigenetic processes control cancer immunotherapy outcomes. We welcome submissions addressing basic, translational, and clinical aspects of immuno-epigenetics.Areas of interest include, but are not limited to:• Tumor-Intrinsic Epigenetic Regulation: Mechanisms by which DNA methylation, histone modifications, and chromatin remodelers control the expression of immune checkpoints (e.g., PD-L1, CTLA-4) and antigen-presenting machinery (e.g., MHC molecules) in cancer cells.• Epigenetics of the Tumor Microenvironment: Epigenetic reprogramming and lineage commitment of immune cells within the TME, including T-cell exhaustion, macrophage polarization, and the activation of myeloid-derived suppressor cells.• Extrachromosomal DNA and Chromatin Topology: The role of extrachromosomal circular DNA (ecDNA), circular RNAs, and altered three-dimensional chromatin architecture in driving tumor heterogeneity, immune evasion, and resistance to immunotherapeutic agents.• Epigenetic Biomarkers for Patient Stratification: Discovery and validation of epigenetic and epigenomic signatures (e.g., cell-free DNA methylation, histone marks) that predict response or resistance to checkpoint inhibitors, adoptive cell therapies, or cancer vaccines.• Combination Treatment Strategies: Preclinical and clinical evaluation of novel combination regimens pairing epigenetic drugs (such as DNMT inhibitors, HDAC inhibitors, or BET inhibitors) with immunotherapies to overcome therapeutic resistance.• Advanced Epigenomic Technologies: Application of single-cell epigenomics, spatial epigenomics, Hi-C, and multi-omic integration to map the dynamic chromatin landscapes associated with immunotherapy response. Topic editors: Preethi Jampala, Evanthia T Roussos Torres Source: https://www.frontiersin.org/research-topics/86140/epigenetic-mechanisms-of-cancer-immunotherapy-response-and-resistance