Peripheral Nerve-Cancer Interactions in the Tumor Microenvironment: A Three-Dimensional Framework Integrating...

The nervous system has emerged as a critical regulator of tumor biology. Over the past 2 decades, accumulating evidence has given rise to the rapidly expanding field of cancer neuroscience, revealing that neural circuits actively shape tumor initiation, progression, metastasis, prognosis, and therapeutic response. While the nervous system comprises both central and peripheral components, increasing attention has focused on the peripheral nervous system (PNS) as a key mediator of tumor-host interactions within the tumor microenvironment (TME). Autonomic (sympathetic, parasympathetic, and enteric) and sensory neural pathways interact dynamically with tumor cells, immune cells, glial cells, and other stromal components, influencing tumor growth, invasion, metastasis, and immune regulation through diverse cellular and molecular mechanisms. In addition, environmental and patient pathophysiological factors-including environmental stress, psychological states, pain, microbiota, aging, metabolic status, and lifestyle behaviors-can further modulate nerve-cancer interactions and reshape the tumor ecosystem. In this review, we systematically organize PNS-cancer interactions within the TME across 3 integrative dimensions: pathological phenotypes, cellular components, and modes of communication, thereby providing a conceptual framework for understanding the mechanistic landscape of cancer neuroscience. This structured perspective highlights the diverse modalities of nerve-tumor communication, identifies key modulatory factors influencing these interactions, and discusses emerging therapeutic strategies targeting nerve-cancer signaling.