Decoding Pancreatic Cancer Pain: From Tumor-Nerve Crosstalk to Targeted Analgesic Strategies

Pancreatic cancer (PC) remains one of the most lethal malignancies, with pain being a prevalent and debilitating symptom that severely impairs patients' quality of life and independently predicts poorer survival. While historically attributed to tumor mass effects, the mechanisms driving PC pain are far more complex. This review aims to synthesize the current understanding of the intricate biological underpinnings of PC-associated pain and discuss the paradigm shift towards mechanism-based therapeutic strategies. The pathogenesis of PC pain is fundamentally driven by dynamic tumor-nerve interactions. A central mechanism is perineural invasion (PNI), a pathologic hallmark wherein cancer cells infiltrate the perineural space, establishing a specialized "neural niche." Within this niche, bidirectional crosstalk involving cancer cells, Schwann cells, immune cells, and stromal components, which is mediated by neurotrophins, chemokines, and neurotransmitters, drives neural remodeling, neuroinflammation, and peripheral nociceptor sensitization. These peripheral signals subsequently induce central sensitization within the spinal cord and brain, perpetuating chronic, refractory pain. While conventional analgesics and interventions like celiac plexus neurolysis remain the mainstay, their relief is often incomplete and transient, as they fail to address these underlying biological drivers. A therapeutic paradigm shift is underway, moving from symptomatic palliation towards mechanism-based interventions. Emerging strategies, including molecularly targeted inhibitors, neuromodulation, and precision nanomedicine platforms, aim to directly disrupt the fundamental neurobiological pathways of pain. By targeting tumor-nerve crosstalk, neuroinflammation, and pathological neural plasticity, these approaches hold the potential to achieve more effective and durable analgesia, ultimately improving the lives of patients suffering from pancreatic cancer.