Targeting neuroimmune pathways in chronic pain: clinical insights and immunotherapeutic prospects

Chronic pain affects a substantial proportion of the global population and remains a leading cause of disability. Existing treatments largely target neuronal excitability and synaptic transmission, yet durable pain relief is uncommon and safety concerns, particularly those associated with opioids, persist. Converging evidence reframes chronic pain as a disorder maintained by maladaptive neuroimmune interactions across the peripheral and central nervous systems. Microglial activation, cytokine and chemokine signaling, adaptive immune cell contributions, and failures in inflammation resolution collectively shape nociceptor sensitization and central sensitization. Emerging human studies using TSPO-PET imaging, alongside increasingly sophisticated cerebrospinal fluid immune profiling, are beginning to provide preliminary in vivo evidence of glial activation, although signals remain heterogeneous across syndromes and point toward immune endotypes. Early clinical signals from repurposed immunomodulators, including anti-TNF agents, colony-stimulating factor 1 receptor (CSF-1R) inhibitors, and pro-resolving mediators, suggest that immune-targeted interventions can modify pain-related outcomes. However, effects are variable, and substantial safety and translational barriers remain. Here we synthesize mechanistic and human evidence, highlight key translational bottlenecks, and propose a roadmap toward precision immunotherapy in chronic pain. This approach emphasizes biomarker-guided stratification, mechanism-aligned endpoints, and pragmatic integration into multimodal care.