Tumor-nervous system crosstalk in PDAC: Current landscape, challenges, and future directions

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal and treatment-refractory malignancies worldwide, largely driven by its uniquely desmoplastic and highly innervated microenvironment. Given the striking incidence of perineural invasion and its profound correlation with intractable cancer pain and early recurrence, tumor-nervous system crosstalk has emerged as a pivotal driver of PDAC progression. Neural components-including neurotransmitters, neurotrophic factors, axon guidance molecules, and specific sensory and autonomic networks (e.g., dorsal root ganglia and sympathetic nerves)-do not merely act as passive conduits, but actively orchestrate tumor genesis, metastasis, and immune evasion. Crucially, this neuro-stromal crosstalk actively drives chemoresistance by facilitating the dual-effect remodeling of tumor energy metabolism and detoxification networks. In this comprehensive review, we decode the multidimensional molecular mechanisms and reciprocal signaling cascades underpinning tumor-nervous system crosstalk. We critically evaluate the translational challenges of applying neurotherapy in clinical practice, encompassing mechanistic pleiotropy, neural plasticity, and visceral safety risks. Furthermore, by synthesizing emerging clinical trials targeting neurotransmitter axes, dorsal root ganglia, and neurotrophic signaling, we provide a forward-looking roadmap for integrating precision neuro-oncology with standard regimens to simultaneously alleviate cancer pain and overcome therapeutic resistance in PDAC.