Macrophages as central mediators of perineural invasion in cancer: Implications for pain and prognosis.

Perineural invasion (PNI) is associated with tumor progression, therapeutic resistance, and poor prognosis. However, the mechanisms driving tumor-nerve interactions remain incompletely understood. Emerging evidence suggests that macrophages function as key regulators within the perineural niche by linking inflammation, neural remodeling, extracellular matrix reorganization, and immunometabolic signaling. This review proposes a macrophage-centered framework for understanding PNI progression and summarizes macrophage-mediated mechanisms involved in nerve invasion, perineural homeostasis disruption, and tumor-nerve crosstalk. We further discuss recent advances in macrophage-targeted therapeutic strategies and highlight current challenges, including limited direct evidence and barriers to clinical translation. Understanding macrophage-mediated PNI may provide new insights into therapeutic interventions targeting the neural-tumor-immune microenvironment.