Nerve Adaptations in the Tumor Microenvironment: A Scoping Review

Introduction: The tumor microenvironment (TME) is a heterogeneous system composed of cancer cells, stromal cells, immune cells, and neural elements. Recent evidence highlights the crucial role of peripheral and autonomic nerve terminals in regulating tumor growth, metastasis, and therapy resistance. However, what remains relatively underexplored is the reciprocal influence of cancer on the nervous system itself. Emerging evidence suggests that cancer cells induce structural, functional, and molecular adaptations in adjacent nerve terminals, pointing to a bidirectional and adaptive communication within the TME. Understanding these nerve adaptations is essential to fully delineate the neurobiology of cancer and identify novel therapeutic targets.Objective: The objective of this scoping review is to systematically map existing literature on cancer-induced adaptations in the nervous system and to explore current understanding of chemical signaling and morphological changes in neural elements within the TME.Methods: We conducted a comprehensive literature search across databases including MEDLINE, Ovid Embase, and Web of Science Core Collection. Additionally, gray literature sources such as Google Scholar (screening up to 20 pages), Elicit, and Connected Papers were explored. We included studies involving animal models, primary and immortalized cell lines, and patient-derived observational studies that focused on cancer-neuron interactions and subsequent neural adaptations. Only articles published in English were considered, with no restrictions on publication date. Article selection and data extraction were performed independently by two reviewers, and findings were reported descriptively.Conclusion: By mapping the current landscape of research on cancer-induced nerve adaptations, this review aims to consolidate fragmented evidence and provide insights into the bidirectional crosstalk between nerves and tumors. Through this review, we aim to enhance current understanding of nerve adaptations in the TME and encourage further exploration in this emerging area of cancer research.