Targeting Neuropilin-1 for Cancer Pain Treatment: A Trial With Potential for Clinical Translation

Cancer-associated pain is common, debilitating, and increasingly recognized not merely as a symptom but as an active participant in disease progression. Its etiology reflects a dynamic convergence of tumor-derived secretory factors, therapy-induced biochemical alterations, and a persistently inflamed tumor microenvironment (TME). Neuropilin-1 (NRP1), a transmembrane co-receptor with broad ligand specificity, has emerged as a key integrator of these diverse pro-nociceptive signals. This review examines how NRP1 coordinates pain pathways triggered by tumor-secreted mediators-including nerve growth factor (NGF), vascular endothelial growth factor A (VEGFA), and hepatocyte growth factor (HGF). We narratively reviewed its role in assembling signaling complexes, particularly with NGF and TrkA, that amplify nociceptive transduction. The therapeutic rationale for targeting NRP1 with biologic and small-molecule inhibitors is analyzed, with emphasis on combining these agents with conventional opioids. Such combination strategies aim to achieve multi-mechanistic analgesia, reduce opioid-related side effects, and interrupt the reciprocal reinforcement between pain signaling and the TME. Finally, we narratively reviewed translational progress, identify persistent challenges, and outline future directions for NRP1-targeted interventions in this complex syndrome.