Tumor-Driven Innervation: Neoneurogenesis, Neural Mimicry, and Neuro-Immune Crosstalk in the Tumor Microenvironment

Cancer is increasingly understood as a tissue- and system-level disease shaped by dynamic interactions among malignant cells, stromal elements, the vasculature, the immune system, and the nervous system. In this context, tumors are not passive recipients of neural input, but active participants in the recruitment, remodeling, and exploitation of neural circuits that support tumor initiation, progression, metastasis, immune evasion, and resistance to therapy. Emerging work in cancer neuroscience has therefore shifted the field from a neuron-centric perspective toward an integrated model of the tumor microenvironment in which malignant cells help establish pathogenic neural niches. This review adopts a tumor-centric perspective to examine how cancer cells drive neoneurogenesis, engage in perineural invasion, and co-opt neural signaling and neuro-immune crosstalk to promote disease progression. It first distinguishes tumor-induced nerve growth and remodeling from perineural invasion as related but mechanistically distinct processes, then considers how tumor cell plasticity and neural mimicry enable malignant cells to acquire neuronal-like traits and exploit neural pathways. The review further explores how tumor-driven innervation shapes angiogenesis, immune modulation, therapeutic resistance, and minimal residual disease while also assessing emerging strategies designed to therapeutically target the tumor–nerve axis. By integrating these themes, the review highlights innervation not as a secondary feature of cancer, but as an active and potentially actionable dimension of tumor biology.