Natural Medicines Modulating Tumor Perineural Invasion: Regulatory Mechanisms and Therapeutic Potential

Perineural invasion (PNI) is a critical pathological hallmark of multiple solid malignancies, which drives tumor progression, distant metastasis, intractable clinical symptoms and poor patient prognosis. Complex tumor-nerve crosstalk and sophisticated molecular networks greatly limit the development of targeted anti-PNI therapies. Natural medicines, featured by structural diversity, multi-target regulatory properties and generally favorable safety profiles, have attracted extensive attention for their potential to disrupt PNI-related signaling and malignant tumor-nerve interactions. This review systematically summarizes representative plant-derived and animal-derived natural compounds with reported anti-invasive or anti-migratory activities relevant to PNI, and comprehensively elaborates their multifaceted mechanisms, including PNI-associated signaling modulation, tumor microenvironment remodeling, inhibition of tumor cell adhesion to and migration along nerves, regulation of tumor proliferation and apoptosis, as well as neural microenvironment homeostasis maintenance. Notably, most available evidence is derived from conventional migration, invasion, or EMT assays rather than PNI-specific experimental models; direct evidence from nerve-tumor co-culture systems or in vivo PNI models remains limited, and no clinical data have been reported to date. The current challenges in this field and prospective directions for further basic research and clinical translation are also highlighted. This review intends to offer theoretical references and rational clues for the development of natural medicines-based anti-PNI therapeutic strategies, while emphasizing the need for rigorous validation in PNI-specific preclinical models and eventual clinical investigation.