Tumors do not communicate only with immune cells, blood vessels, and stromal tissue. A growing body of evidence suggests that cancer can also co-opt the nervous system, reshaping the tumor microenvironment in ways that support growth, invasion, immune escape, and therapeutic resistance. A new review published in Research by researchers from Zhejiang Provincial People's Hospital and collaborating institutions focuses on peripheral nerve–cancer interactions and proposes a three-dimensional framework for understanding this emerging field.

The peripheral nervous system includes sympathetic, parasympathetic, enteric, and sensory pathways. Under normal physiological conditions, these neural systems help regulate organ function, tissue repair, pain, immune balance, and local homeostasis. Tumors, however, can exploit these functions. The review argues that nerve–cancer interactions should not be understood only as tumor invasion into nerves. Instead, they include a broad spectrum of processes in which tumors remodel nerves, recruit neural inputs, induce neuropathy, and hijack neural circuits that extend beyond the local tumor site.

The first dimension of the framework concerns pathological phenotypes. The review organizes peripheral nerve–cancer interactions into perineural invasion, tumor neurogenesis and innervation, cancer-induced neuropathy, and long-distance neural regulation. Perineural invasion is a well-recognized route of tumor spread and is often associated with aggressive disease and poor prognosis. Tumor innervation describes the growth or remodeling of nerve fibers within the tumor microenvironment, where nerves can release neurotransmitters and neuropeptides that shape tumor and immune behavior. Cancer-induced neuropathy highlights how tumors can damage nerves even without direct invasion, while long-distance neural regulation shows how cancer may co-opt brain–body or inter-organ neural circuits to reshape immunity and metabolism.

The second dimension focuses on cellular components. Nerves can act directly on tumor cells, but they can also regulate cancer indirectly through Schwann cells, enteric glial cells, macrophages, T cells, fibroblasts, endothelial cells, and other stromal or immune intermediates. The review also broadens the field by discussing neuronal mimicry, in which cancer cells or cancer stem cells acquire neuron-like properties. In such cases, tumors may use neurotransmitter-related or electrophysiological programs to promote proliferation, invasion, immune suppression, or treatment resistance, even when classical nerve fibers are not the only source of neural-like signaling.

The third dimension addresses modes of communication. Nerve–tumor signaling can occur through diffuse biochemical communication involving neurotransmitters, neurotrophic factors, neuropeptides, cytokines, chemokines, and extracellular vesicles. These signals may be slower and more sustained, shaping the local tumor ecosystem over time. More recent discoveries have added a faster and more spatially precise layer: functional synapses or pseudo-synapses can form between neurons and tumor cells, and tunneling nanotubes may allow neurons to transfer organelles such as mitochondria to cancer cells. These findings shift the concept of tumor innervation from simple anatomical proximity to active functional communication.

The review also emphasizes that nerve–cancer interactions are shaped by patient and environmental factors. Psychological stress, positive emotional states, environmental temperature, pain, microbiota, aging, obesity, smoking, diet, exercise, and circadian disruption may all influence neural signaling in the tumor microenvironment. Chronic stress, for example, can enhance sympathetic output and reinforce tumor innervation, while cancer-associated pain may actively participate in tumor progression through sensory nerve–immune pathways rather than serving only as a symptom.

Therapeutically, the review discusses denervation, neurotransmitter blockade, neurotrophic signaling inhibition, neural–immune combination therapy, psychosocial interventions, and cancer pain management. Some β-adrenergic and neurotrophic pathway-targeted strategies have already entered clinical or translational evaluation, but the article cautions that neural targeting is highly context-dependent. The same neural pathway may have different effects across tumor types, nerve subtypes, receptor profiles, and immune states. The broader significance of the review is therefore not to propose a single universal treatment, but to provide a framework for stratifying nerve–cancer mechanisms and developing more precise neural-targeted cancer therapies.

The complete study is accessible via DOI:10.34133/research.1221