The CB₂ Receptor in Immune Regulation and Disease: Genetic Architecture, Epigenetic Control, and Emerging Therapeutic Strategies

The cannabinoid receptor type 2 (CB₂) is gaining recognition as a critical regulator of immune equilibrium, neuroinflammation, and tissue repair processes. Unlike its counterpart, the CB₁ receptor, which produces psychoactive effects when activated, the CB₂ receptor presents itself as a more appealing and safer target for therapeutic interventions. This review investigates the genetic and epigenetic regulation of CB₂ receptor and examines how its signaling affects both immune and nervous system cells. We emphasize its influence on microglial activity, the modulation of immune responses, and its regulation by non-coding RNAs and chromatin remodeling. Through these pathways, CB₂ receptor plays a significant role in various disease processes, with increasing evidence connecting it to depression, chronic pain, schizophrenia, inflammatory conditions such as asthma and colitis, and even cancer immunotherapy. We also explore how CB₂ receptor interacts with components of the endocannabinoid system, including Transient Receptor Potential (TRP) channels, prostanoids, and Peroxisome proliferator-activated receptors (PPARs). Lastly, we analyze how innovative therapies targeting CB₂ receptor, such as selective agonists, positive allosteric modulators (PAMs), and biased ligands, could pave the way for more precise and effective treatments for neurological, inflammatory, and immune-related disorders.