The peripheral nervous system can affect tumors through electrical, chemical, and trophic signals. Nerve fibers release neurotransmitters and neuropeptides that bind to receptors on cancer cells, triggering intracellular pathways associated with proliferation, migration, survival, and invasion. Depending on the tumor type and neural context, signaling molecules such as norepinephrine, acetylcholine, dopamine, substance P, and other neuroactive factors may alter gene expression and cellular behavior. These interactions can also influence blood-vessel formation and the activity of surrounding stromal cells, helping establish conditions that support tumor expansion.

The communication is not one-directional. Tumors can actively attract, stimulate, and reorganize nearby nerves, creating a feedback loop that may intensify disease. Cancer cells and stromal cells can produce nerve growth factor and other neurotrophic signals, including brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. These molecules encourage the survival, branching, and extension of axons into tumor tissue. As new nerve fibers enter the tumor microenvironment, they provide additional sources of signaling molecules, potentially reinforcing malignant behavior and making the tumor increasingly integrated with local neural circuits.

The review identifies three interconnected processes as central to nerve–tumor biology: perineural invasion, axonogenesis, and neurogenesis. Perineural invasion occurs when cancer cells migrate along or into existing nerves, a phenomenon frequently associated with local recurrence, severe pain, and poor clinical outcomes. Axonogenesis describes the growth of new nerve fibers toward and within tumors. Neurogenesis, more broadly, refers to the formation of new neural connections or neural-like networks in the tumor environment. Although these mechanisms are distinct, they can operate together, providing tumors with routes for invasion and a continually expanding system of biological communication.

Perineural invasion is particularly important in cancers of the pancreas, head and neck, prostate, stomach, and colon. Malignant cells may adhere to nerve structures, degrade surrounding barriers, and move through spaces formed by the protective layers of nerves. This process can allow tumors to spread beyond their visible margins, complicating surgery and increasing the risk of recurrence. At the same time, nerve injury caused by invasion may release inflammatory and growth-promoting signals. The result is a potentially self-reinforcing cycle in which neural damage, inflammation, and cancer-cell migration contribute to increasingly aggressive disease.

Neural signaling also reaches far beyond the cancer cell itself. Neurotransmitters and neuropeptides can modify immune-cell recruitment, suppress antitumor immune responses, and change the behavior of cancer-associated fibroblasts. They may influence endothelial cells and vascular smooth-muscle cells, affecting blood-vessel development and tumor perfusion. This neuro-immune crosstalk is especially significant because immune suppression is a defining feature of many tumor microenvironments. By altering the balance between inflammatory and antitumor activity, neural signals may help malignant cells evade immune surveillance while maintaining access to nutrients and oxygen.

These findings are creating interest in therapies that interfere with nerve-dependent tumor support. Researchers are investigating whether blocking specific neurotransmitter receptors, inhibiting neurotrophic factors, or disrupting the growth of tumor-associated nerves can slow cancer progression. Existing neuroactive medicines, including drugs that affect adrenergic, cholinergic, or neuropeptide signaling, are being considered for possible repurposing in oncology. However, the biological effects of neural pathways are highly context-dependent. A treatment that blocks one nerve signal in a particular cancer may have limited value in another, making patient selection and molecular profiling essential for future clinical development.

The nerve–tumor axis may also offer a way to address one of the most difficult symptoms of cancer: persistent pain. Perineural invasion and tumor-associated nerve growth can sensitize sensory neurons, while inflammatory mediators released by cancer and immune cells can amplify pain transmission. Nerve-targeted interventions could therefore have two possible benefits—reducing tumor-supportive signaling and relieving symptoms. The challenge will be to distinguish neural pathways that promote malignancy from those required for normal tissue function, sensation, and repair. Precision approaches will be necessary to avoid unwanted neurological effects.

New technologies are rapidly improving scientists’ ability to investigate these interactions. Single-cell RNA sequencing can reveal the molecular identities of nerve cells, cancer cells, immune populations, and stromal cells within the same tumor. Spatial transcriptomics adds information about where those cells and their signals are located, showing how neural structures are positioned relative to invasive tumor fronts or immune-suppressed regions. Neural tracing, advanced microscopy, organoid systems, and experimental models can further track the movement of nerve fibers and test how specific signals affect tumor behavior. Together, these tools are turning the nerve–tumor axis from an overlooked concept into a measurable and potentially targetable feature of cancer biology.

The review by Liangzhan Sun and colleagues presents nerve–tumor interactions as a transformative frontier for oncology. Its central message is that cancer progression is shaped not only by mutations inside malignant cells but also by the communication networks surrounding them. Understanding how nerves enter tumors, how tumors manipulate neural tissue, and how neural signals influence immunity and metastasis could lead to new diagnostic markers and combination treatments. As research advances, the nervous system may become an important target in cancer therapy—offering a new route to limit tumor growth, overcome treatment resistance, and improve the quality of life of patients living with cancer.

Subject of Research: Nerve–tumor interactions and the role of neural signaling in cancer progression, metastasis, treatment resistance, the tumor microenvironment, and cancer-associated pain.

Article Title: Understanding nerve–tumor interactions: From basic biology to therapeutic innovation

Web References: https://doi.org/10.1016/j.gendis.2025.101955

References: Liangzhan Sun, Xia Li, Yaxuan Wang, Jingxuan Wang, Renrui Xie, Ningyi Zhang, and Zemin Zhang, “Understanding nerve–tumor interactions: From basic biology to therapeutic innovation,” Genes & Diseases, Volume 13, Issue 4, 2026, Article 101955.

Image Credits: Genes & Diseases

Keywords: nerve–tumor axis, cancer neuroscience, tumor microenvironment, perineural invasion, axonogenesis, neurogenesis, neurotransmitters, neuro-immune crosstalk, cancer metastasis, cancer pain, therapeutic innovation

This investigative endeavor focused on the intricate communications within the tumor microenvironment, a complex cellular ecosystem surrounding cancer cells. While the immune system’s cellular constituents have long been studied for their roles in either suppressing or facilitating tumor growth, the influence of nervous system components has remained enigmatic. The Crick Institute team addressed this gap by examining how specialized sensory nerves, which typically detect environmental threats such as noxious heat, physical damage, or chemical irritants, interact with immune cells within lung tumors.

Utilizing sophisticated mouse models, the researchers meticulously manipulated the activity of these sensory nerves, observing pronounced effects on tumor dynamics. Notably, sensory nerve activation bolstered tumor growth, whereas their inhibition correlated with reduced cancer progression. This bidirectional relationship was further characterized by the tumors’ capacity to induce nerve proliferation and stimulate the release of the neuropeptide calcitonin gene-related peptide (CGRP), a key molecular mediator in this neuroimmune dialogue.

CGRP emerged as a crucial suppressor of immune defense mechanisms in the tumor milieu. The study demonstrated that CGRP acts on tumor-associated macrophages, immune cells integral to the orchestration of antitumor responses, impeding the formation of tertiary lymphoid structures (TLS). TLS are organized clusters of immune cells renowned for their association with improved patient prognosis across various cancers, including lung carcinoma. By hindering TLS development, CGRP effectively diminishes the immune system’s capacity to mount a robust and coordinated attack against neoplastic cells.

Importantly, therapeutic interventions that either disrupted the sensory nerve signals or blocked CGRP receptors reinstated TLS formation within tumors. This immunological restructuring intensified the antitumor immune response, resulting in substantial suppression of tumor growth. Given that CGRP receptor antagonists are already utilized clinically for the treatment of migraine headache, the translational potential of repurposing these drugs for cancer therapy is both compelling and immediate.

Extending their inquiry to environmental factors, the Crick team explored the impact of cigarette smoke—a dominant risk factor for lung cancer—on this neuroimmune interface. Exposure to cigarette smoke extract was found to amplify sensory neuronal activity, thereby accelerating tumor advancement. This insight reveals an understudied pathway by which smoking exacerbates cancer progression, beyond its well-known genotoxic effects, by harnessing nerve-mediated immune suppression.

The implications of these findings extend far beyond a single malignancy. They challenge the classical paradigms of tumor immunology by integrating neuroscience, illustrating that nerve fibers and their signaling molecules are not merely bystanders but active architects in the tumor microenvironment. This intersection of disciplines suggests that cancer treatment strategies could be revolutionized by targeting neuroimmune interactions, thereby enabling modulation of the immune landscape in favor of tumor eradication.

Leanne Li, leading the Cancer-Neuroscience Laboratory at the Crick Institute, emphasized the transformative potential of these discoveries: “Our work underscores the complexity of the tumor microenvironment, revealing how neuronal components influence immune cell behavior and tumor progression. This intersection of neuroscience and immunology represents a fertile ground for innovative therapeutic development.”

Co-first authors Ya-Hsuan Ho and Giacomo Bregni further highlighted the clinical ramifications of the study. Ho noted, “Our observations that neuronal activity can reorganize the immune architecture within tumors challenge existing concepts of immune evasion in cancer.” Bregni added, “Despite advancements in immunotherapy, many lung cancer patients do not benefit due to resistance mechanisms. Targeting neuroimmune pathways offers a previously unrecognized strategy to enhance treatment responses.”

This research serves as the foundation for future work by the InteroCANCEption team, an interdisciplinary consortium funded with up to £20 million through the Cancer Grand Challenges initiative. Their mission is to decode how the nervous system’s sensory capabilities—interoception—detect tumors and modulate cancer progression. By mapping neural pathways and brain activity patterns linked to tumor signaling, the team aims to translate neurobiological insights into novel diagnostics and therapies encompassing neural modulation techniques.

Dr. David Scott, Director of Cancer Grand Challenges, reflected on the significance of harnessing the nervous system to intervene in cancer development: “Exploring how brain-tumor communications influence disease offers an exciting frontier. Funding teams like InteroCANCEption catalyzes transformative breakthroughs that redefine the boundaries of oncology and neuroscience.”

The revelation that sensory neurons and their secreted factors contribute dynamically to immune suppression within tumors not only reshapes our understanding of lung cancer biology but also signals a turning point in cancer research. Therapeutic targeting of neuroimmune crosstalk, particularly leveraging existing pharmacological agents that inhibit CGRP signaling, holds promise for augmenting immunotherapy efficacy, which remains suboptimal for many patients.

Moreover, the identification of cigarette smoke’s role in modulating this neuroimmune nexus provides a molecular explanation for the exacerbation of lung cancer progression by smoking. This newfound knowledge underlines the urgency of integrating preventative measures with innovative therapeutic strategies to confront lung cancer—a disease that continues to pose substantial global health challenges.

In summary, the Francis Crick Institute’s landmark study charts a new path by elucidating how sensory nerve signals regulate immune architecture in lung cancer and identifying CGRP as a key inhibitory messenger. The potential to repurpose CGRP receptor antagonists to reinvigorate antitumor immunity offers a compelling translational direction. As neuroscience and immunology converge, future cancer treatments may harness the nervous system’s influence to tip the balance against malignancy, transforming patient outcomes in the years to come.

Subject of Research: The neuroimmune interactions between sensory nerves and immune cells within the lung tumor microenvironment and their implications for cancer progression and therapy.

Article Title: Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer.

News Publication Date: Tuesday, May 19, 2026.

References: Ho et al. (2026). Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer. Cell.