Chronic cancer pain results from the complex interaction of nociceptive, neuropathic, and neuroimmune mechanisms, which vary according to tumor type, location, stage, and treatment history. Recent advances in cancer neuroscience have reframed pain as a dynamic manifestation of reciprocal tumor–nerve–immune interactions, rather than a mere consequence of tissue damage. In this model, malignant, stromal, and immune cells remodel nociceptive circuits at peripheral and central levels. This narrative review, conducted in accordance with SANRA criteria, synthesizes current mechanistic insights into the neurobiology of cancer pain. At the peripheral level, tumor-derived mediators such as prostaglandins, cytokines, chemokines, glutamate, and endothelin-1 drive nociceptor sensitization via G-protein–coupled and tyrosine kinase pathways. In bone metastases, osteoclast-mediated resorption generates an acidic microenvironment that activates acid-sensing ion channels and transient receptor potential (TRP) channels, linking skeletal destruction with movement-evoked pain. Pathological nerve remodeling and perineural invasion further contribute to neuropathic components and adverse oncological outcomes. Treatment-induced syndromes, notably chemotherapy-induced peripheral neuropathy, result from axonal injury, mitochondrial dysfunction, and neuroinflammation. At the central level, persistent afferent input induces glial activation and chemokine signaling, amplifying synaptic transmission and promoting central sensitization. Emerging evidence also highlights epigenetic regulation, noncoding RNAs, and tumor–immune–neural crosstalk as potential therapeutic targets. Collectively, these findings position cancer pain as a disorder of aberrant tumor–nerve–immune signaling. Effective management requires precision strategies integrating mechanism-guided pharmacology, neuromodulation, and supportive care. This review emphasizes the need for translational research to bridge mechanistic discoveries with personalized, multimodal interventions in oncology.
