Nerve Adaptations in the Tumor Microenvironment

ABSTRACT The tumor microenvironment (TME) is a complex ecosystem composed of cancer cells, stromal components, immune infiltrates, and neural elements. The presence and growth of nerves within or in close association with tumor tissue, a phenomenon known as tumor innervation, has long been observed. However, recent evidence supports a more active role for peripheral nerves in regulating cancer growth, metastasis, and therapeutic resistance. What remains underappreciated is the reciprocal influence of cancer cells on the nervous system. Accumulating data indicate that cancer cells remodel adjacent nerve terminals, triggering structural, neurochemical, bioelectrical, and transcriptional changes in a tumour‐type‐specific manner. These adaptations resemble pathways observed in nerve regeneration and suggest a tightly regulated, bidirectional signaling axis between cancer and nerves. In this review, we systematically consolidate emerging literature describing these nerve adaptations and categorize them across multiple levels, from morphological remodeling and neurotransmitter shifts to bioelectrical signaling and neuroimmune crosstalk. We highlight the central role of the tumor secretome in mediating nerve‐cancer communication and emphasize how neural elements actively shape tumor behavior. By consolidating and critically examining findings across diverse cancer models and experimental systems, this review provides a mechanistic framework for understanding neural remodeling in cancer and identifies key areas for future investigation, including the potential of targeting nerve–tumor interactions as a therapeutic strategy.