Innate Immune Surveillance and Recognition of Epigenetic Marks

The innate immune system protects against infection and cellular damage by recognizing conserved Pathogen-Associated Molecular Patterns (PAMPs) and Damage-associated Molecular Patterns (DAMPs). Emerging evidence suggests that aberrant epigenetic modifications – such as altered DNA methylation and histone marks – can serve as immunogenic signals that activate pattern recognition receptor (PRR)-mediated immune surveillance. This review explores the concept that epigenetic marks may function as DAMPs or even mimic PAMPs. We highlight how unmethylated CpG motifs, typically suppressed by host methylation, are recognized as foreign by Toll-like receptor 9 (TLR9). We also examine how cytosolic DNA sensors, including cGAS, detect mislocalized or hypomethylated self-DNA resulting from genomic instability. In addition, we discuss how extracellular histones and nucleosomes released during cell death or stress can act as DAMPs that engage TLRs and activate inflammasomes. In the context of cancer, we review how epigenetic dysregulation can induce a “viral mimicry” state, where reactivation of endogenous retroelements produces double-stranded RNA sensed by RIG-I and MDA5, triggering type I interferon responses. Finally, we address open questions and future directions, including how immune recognition of epigenetic alterations might be leveraged for cancer immunotherapy or regulated to prevent autoimmunity. By integrating recent findings, this review underscores the emerging concept of the epigenome as a target of innate immune recognition – bridging the fields of immunology, epigenetics, and cancer biology.