Decoding neuro-tumor interactions in pancreatic cancer: mechanisms, immunosuppressive networks and therapeutic opportunities

Proposes a unified four-stage mechanistic model of PNI linking mutual chemotaxis between tumors and nerves, adhesion and invasion at the tumor-nerve interface, extracellular matrix remodeling, and neural plasticity alterations into one continuous process. Where PNI was historically regarded as a passive route for tumor dissemination, the model reframes it as a multicellular process involving bidirectional crosstalk among cancer cells, nerve fibers, stromal cells, and immune components in the tumor microenvironment. A review-level synthesis of current research advances; the text notes PNI is detected in 80%-100% of PDAC patients and serves as an independent adverse prognostic factor.

Defines the perineural invasion microenvironment as a neuro-immune privileged sanctuary and delineates its multicellular composition and pathological consequences. Elevates the spatial relationship among nerves, immunity, and tumor into a distinct microenvironment concept with immune-evasion function, rather than mere anatomical proximity. A review-level synthesis describing cellular composition and pathological significance based on current research advances.

Summarizes therapeutic strategies targeting the neuro-immune-tumor axis and ongoing clinical trials, and discusses translational challenges. Translates mechanistic understanding into actionable intervention directions spanning neural, immune, and tumor targets. A synthesis of existing therapeutic strategies and ongoing clinical trials, presented as directional summary rather than results of a single trial.

Highlights transformative applications of multi-omics technologies and artificial intelligence in PNI diagnosis, mechanistic discovery, and therapeutic optimization. Introduces computational and data-driven approaches into the PNI research pipeline, pointing to new paths for diagnosis and treatment optimization. Presented as a forward-looking outlook; no specific model performance or dataset results are given in the text.

The framework is intended for basic and translational researchers working on pancreatic ductal adenocarcinoma, particularly perineural invasion, and for clinical researchers interested in the neuro-immune-tumor axis; its setting is as a theoretical reference for mechanistic understanding and therapeutic target screening, not for direct patient stratification or efficacy prediction.

The causal ordering and relative weight of the stages in the four-stage model still await experimental verification; the consistency of the specific cellular and molecular composition of the neuro-immune privileged sanctuary across patients remains unclear; and the specific performance metrics of the clinical trials, multi-omics, and artificial intelligence applications mentioned are not provided in the text, so readers should consult the original studies for verification.