The paradigm shift from molecular oncology to systems medicine reconceptualizes cancer from aberrant proliferative tissue to a pathological organ with systemic ramifications. This establishes a novel framework at the intersection of oncology and neurobiology, investigating neuro-tumor interactions through the innervation context of the anatomical site or organ harboring the tumor. The concept that cancer is a systemic disease involving neural regulation is now widely recognized 1. Continuous advances in molecular biology have significantly propelled oncological research; oncology has shifted focus from intratumoral mechanisms to the tumor microenvironment 2. Importantly, viewing tumors as self-regulating pseudo-organs rather than mere tissues to investigate their systemic effects offers a novel perspective on tumor biology 1. Currently, research on intratumoral neural infiltration primarily focuses on molecular mechanisms, which holds advantages. However, a more macroscopic and holistic research perspective is needed for neural innervation 3. We propose that organs serve as the fundamental biological units for understanding cancer neuroscience (Figure 1). Organ is the basic unit of tumor nerve research because of the organ heterogeneity of tumor innervation 4, 5. Central neoplasms such as glioblastoma instead hijack existing neurons, forming functional synapses that drive activity-dependent proliferation 6. While peripheral neoplasms (pancreas, breast, etc.) recruit mainly peripheral autonomic (sympathetic/parasympathetic) and sensory nerves via axonogenesis and perineural invasion to foster a pro-tumor milieu. Visceral tumors (liver, colorectum) receive dual autonomic supply and exploit metabolic-neural coupling (e.g., vagal sensing of portal-osmolarity) or cholinergic/adrenergic imbalance to propel growth 7. Somatic tumors (skin, soft-tissue sarcoma) display segmental somatic-sensory innervation (TRPV1+/CGRP+ fibers) conveying sharp pain and mechanosensation, with scarce autonomic input 8. As tumor immunology has evolved from the generalized immune evasion paradigm to a framework of organ-specific immune environments, an organ-based approach is similarly beneficial for comprehending and overcoming cancer. Neural infiltration and neural innervation represent distinct states within tumors. Compared to adjacent normal tissue, solid tumors exhibit significant hyper-innervation, characterized by increased nerve fiber density, aberrant branching patterns, and dysfunction 9, 10. This process is termed axonogenesis or sprouting, involving chemotactic attraction of adjacent nerve terminals by tumor-secreted neurotrophic factors (e.g., NGF, BDNF, Artemin) and axon guidance molecules (e.g., Netrin-1, EphrinB1), inducing axonal growth from dorsal root ganglia (DRG) and autonomic ganglia into the tumor parenchyma 6, 11. Different organs exhibit distinct peripheral neural innervation backgrounds 4, 5. Visceral organs (pancreas, prostate, lung, gallbladder) receive dense dual autonomic innervation (sympathetic adrenergic fibers and parasympathetic cholinergic fibers) along with sensory nerve fibers, whereas somatic tissues (skin, breast, oral mucosa) are primarily innervated by sensory nerves with sparse autonomic distribution 4. These distinct neural backgrounds give rise to different dependencies: prostate and pancreatic adenocarcinomas exhibit “autonomic addiction,” with sympathetic nerves driving early tumorigenesis via β-adrenergic signaling and parasympathetic nerves promoting metastatic dissemination through muscarinic receptors 12. In contrast, cutaneous malignancies (melanoma, basal cell carcinoma) and breast cancer rely primarily on sensory neuron-derived neuropeptides (substance P, CGRP) for growth and invasion 5. Crucially, the developmental origin of tumors dictates their neuro-interactome 13. Organs of endodermal origin (pancreas, biliary tract) and mesodermal urogenital tissues retain the plasticity to recruit autonomic precursor cells, while tumors of ectodermal origin hijack existing sensory neural structures 14. Studies have found that the degree of neural infiltration significantly correlates with lymph node metastasis and organ metastasis, suggesting that neural invasion may contribute to the construction of a metastatic niche 15. Across diverse solid tumors such as breast, prostate, and pancreatic cancer, intratumoural nerve fibers operate not as structural components but as active architects of the innervated TME 16. By releasing neurotransmitters (noradrenaline, acetylcholine) and sensory neuropeptides (CGRP, substance P), they establish neuro-tumor synapse-like connections that promote proliferation, suppress apoptosis, and drive angiogenesis. This neural TME is distinctly heterogeneous. Sensory nerves employ CGRP and substance P to re-sculpt immunity: in melanoma, nociceptor-derived CGRP engages RAMP1 on CD8⁺ T cells, inducing checkpoint expression and exhaustion 17; in pancreatic cancer, CGRP acts on cancer-associated fibroblasts to curtail IL-15 secretion and blunt NK-cell infiltration 13. Conversely, autonomic nerves maintain cancer stemness and foster metastatic dissemination via β-adrenergic and muscarinic receptors, respectively 18. Conceptual advances now frame tumors not merely as collections of mutated cells but as pseudo-organs whose systemic attributes include multi-organ metastatic cascades, cancer-associated cachexia and central neural remodeling, all of which demand organism-level investigation 8. The neural-niche concept, first coined for brain metastasis, is now extended to peripheral organs as pre-metastatic soil 19. Organ-specific neural signatures determine metastatic tropism: sympathetic-rich marrow nurtures prostate-cancer homing, whereas vagal innervation of the liver modulates metabolic adaptation of colorectal metastases 18. Future efforts should map a comprehensive neuro-atlas of solid tumors, annotated by organ. Single-cell profiles of tumor-infiltrating neurons must be classified by anatomy (visceral vs somatic) and developmental layer (endoderm, mesoderm, ectoderm). Comparative studies across organs reveal context-dependent neural rules: parasympathetic signaling promotes gastric cancer yet suppresses pancreatic cancer, underscoring the need to dissect organ-specific mechanisms. Advanced neuro-technologies such as bioelectric neuro-immunotherapy and non-contact brain modulation may potentiate anti-tumor immunity, offering non-pharmacological strategies to reprogram the TME and enhance immune-mediated tumor control 20. These cutting-edge neuro-techniques create opportunities for precision oncology by enabling non-pharmacological reprogramming of the TME and for strengthening immune-mediated tumor control 11. Future integration of neural modulation with conventional therapies is expected to break the deadlock of treatment resistance and trigger a fundamental shift in oncologic practice. Advances in this field will deepen the convergence of oncology, neuroscience, and immunology, offering fresh strategies to defeat cancer. Jingwei Zhao, Zhichao Lu, and Xiaofei Zhi: writing – original draft. Jingwei Zhao, Xiaofei Zhi, and Ziheng Wang: conceptualization. Jingwei Zhao, Zhichao Lu, Zhenyun Duan, and Jiayun Zhu: investigation. Jingwei Zhao, Danyang Shen, Xiaofei Zhi, Wei Gong, Shilei Liu, Hexu Han, and Shiqi Ren: writing – review and editing. The authors have nothing to report. Wei Gong and Ziheng Wang serve as members of the Editorial Board of iMetaMed. They were excluded from editorial decision-making related to the acceptance of this article for publication in the journal. All other authors declare no conflicts of interest. Data sharing is not applicable—no new data generated, or the article describes entirely theoretical research.
Zhao et al. (2026) studied this question.