Radiotherapy-Associated Pain in Head and Neck Cancer: From Clinical Burden to Neuroimmune Modulator

Area of Science:

• Oncology
• Neuroscience
• Immunology

Background:

• Radiotherapy-associated pain is a common complication in head and neck cancer.
• Emerging evidence links pain to tumor biology, immune remodeling, and therapeutic outcomes.
• Sensory nerves are active participants in the tumor microenvironment (TME), influencing antitumor immunity.

Purpose of the Study:

• To review clinical manifestations and biological features of radiotherapy-associated pain in head and neck cancer.
• To explore the role of neuroimmune crosstalk in the tumor immune microenvironment (TIME).
• To discuss the translational significance of pain phenotyping in combined treatment strategies.

Main Methods:

• Review of clinical manifestations of radiotherapy-associated pain (inflammatory, neuropathic, chronic).
• Summary of evidence-based preventive and supportive strategies for oral mucositis.
• Discussion of radiotherapy's impact on the TIME and neuroimmune interactions.

Main Results:

• Radiotherapy reshapes the TIME via immunogenic cell death, cGAS-STING pathway activation, and immune suppression.
• Nociceptive signaling pathways can modulate T-cell and myeloid-cell activity.
• Persistent pain may create an immunosuppressive, wound-like microenvironment affecting treatment response.

Conclusions:

• Radiotherapy-associated pain may be a neuroimmune phenotype, not just an adverse event.
• Pain phenotyping can inform precision management and combined radiotherapy-immunotherapy strategies.
• Opioid-sparing analgesia, neuromodulation, and neuroimmune interventions show promise for symptom control and enhanced antitumor immunity.