bims-netuvo 2026-05-10 papers

bims-netuvo

Biomed News

on Nerves in tumours of visceral organs

Issue of 2026–05–10
thirteen papers selected by
Maksym V. Kopanitsa, Charles River Laboratories

Neural-immune-cancer crosstalk in pancreatic cancer: mechanisms and clinical translation.
Neuro-immune interactions in gastrointestinal oncology: Mechanisms, challenges, and therapeutic potential.
Sensory neurons inhibit invadopodia and metastasis via direct CGRP-RAMP1-cAMP signaling to cancer cells.
The hallmarks of neuro-immune reprogramming in cancer.
A peritumoral microenvironment engaged by Reg-EXTL3 axis fosters nerve-cancer interactions in pancreatic ductal adenocarcinoma.
Perineural invasion in solid tumors: biological foundations and the emerging integration of machine learning and artificial intelligence.
The role of γ-aminobutyric acid and its receptor in metabolic reprogramming and tumor progression.
Pancreatic cancer fibrosis activates protumorigenic Schwann cells through a nuclear mechanosensing mechanism.
Editorial Expression of Concern: Nociceptive neurons promote gastric tumour progression via a CGRP-RAMP1 axis.
Tumor size and vascular and perineural invasion predict mesenteric involvement in small-intestinal neuroendocrine tumors.
Disrupting sympathetic nerve-tumor crosstalk via biomimetic nanovesicles to augment chemotherapy efficacy under chronic stress.
Pan-cancer neurotransmitter receptor alterations define neuroregulatory subtypes with prognostic significance.
Advances in mechanisms and treatments of brain metastases.

Front Cell Dev Biol. 2026 ;14 1828946

Neural-immune-cancer crosstalk in pancreatic cancer: mechanisms and clinical translation.

Wenjun Meng, Ping Yao, Manting Wang, Xinyue Pan, Jingzhang He, Yan Tie, Qinqin He, Rujun Zheng.

  Pancreatic cancer remains a persistently high mortality rate, with limited efficacy through traditional therapies, necessitating exploration of its pathogenesis from a new biological perspective. The tumor microenvironment plays a decisive role in the malignant progression of pancreatic cancer, and the nervous system, as a key component of the microenvironment, has an active and bidirectional interaction with tumor cells, known as the "neuro-tumor interaction." Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is highly rich in neural components. The neuro-tumor interaction not only drives the unique neural infiltration of PDAC but also profoundly affects tumor proliferation, invasion, metastasis, immune escape, and pain perception. Recent studies have revealed that tumor cells, Schwann cells, cancer-associated fibroblasts, and immune cells form a "perineural niche" through neurotrophic factors, chemotactic axes, cell adhesion/extracellular matrix remodeling, and neurotransmitters, driving tripartite neural-immune-cancer interaction and providing targets for new therapeutic interventions. This review systematically summarized the key molecular and cellular mechanisms of neural-immune-cancer interactions in pancreatic cancer and specifically discussed several translational strategies, including neurotrophic factor blockade targeting NGF/TrkA and GDNF/RET, myeloid cell reprogramming targeting CXCR2/CXCL to improve T cell infiltration, and potential combination strategies that combine neuromodulatory drugs (e.g., β-blockers or CRGP antagonists) with immune checkpoint inhibitors. These strategies have shown feasibility in preclinical studies or PDAC models and warrant further validation in stratified clinical trials.

Keywords:  neural-immune-cancer crosstalk; neuro-immune axis; pancreatic cancer; pancreatic ductal adenocarcinoma; tumor microenvironment

DOI:  https://doi.org/10.3389/fcell.2026.1828946
Innovation (Camb). 2026 May 04. 7(5): 101300

Neuro-immune interactions in gastrointestinal oncology: Mechanisms, challenges, and therapeutic potential.

Xueying Wang, Wentong Mei, Zifan Wang, Mengmeng Ma, Jianbo Wang, Jiafu Ji, Xiaofang Xing.

  Gastrointestinal (GI) cancers represent a leading cause of cancer-related mortality globally, characterized by a complex tumor microenvironment where bidirectional neuro-cancer-immune interactions critically influence disease progression. The CNS integrates ascending gut-derived signals and transmits descending regulatory responses through distinct autonomic neural pathways, while peripheral sensory, sympathetic, parasympathetic, and enteric neurons modulate innate and adaptive immune cell functions through specialized neurotransmitter circuits. This coordinated neural-immune crosstalk operates within the neuro-endocrine-immune axis, forming an integrated regulatory network that governs tissue homeostasis and tumor surveillance. Emerging evidence demonstrates that neural dysregulation promotes GI tumorigenesis through immunosuppressive mechanisms, while therapeutic neural interventions show promising efficacy in preclinical cancer models. The gut-brain axis represents a paradigmatic framework for understanding how neuroimmune signaling influences cancer progression and metastasis, revealing previously unrecognized diagnostic, prognostic, and therapeutic opportunities. Here, we review the molecular mechanisms underlying neuroimmune interactions in GI cancer pathogenesis and evaluate the therapeutic potential of neurally targeted interventions for cancer management.

Keywords:  gastrointestinal cancer; nervous system; neuro-immune interactions; neuroimmunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.xinn.2026.101300
bioRxiv. 2026 Apr 21. pii: 2026.04.17.719233. [Epub ahead of print]

Sensory neurons inhibit invadopodia and metastasis via direct CGRP-RAMP1-cAMP signaling to cancer cells.

Ines Velazquez-Quesada, Elizaveta Belova, Afrooz Jarrah, Maria Carolina Cesar Mariano, Yasmine Dahleh, Maíra de Assis Lima, Debora Barbosa Vendramini Costa, Ralph Francescone, Edna Cukierman, Louis Hodgson, Bojana Gligorijevic.

Breast cancer is globally the most common cancer among women. Although the five-year survival rate exceeds 80% for patients with localized disease, it drops to approximately 30% once metastasis occurs, underscoring the urgent need to define mechanisms that drive metastatic progression. Breast is a highly innervated organ and most of its innervation is sensory. However, whether sensory neurons can directly impact breast cancer cells remains an understudied topic. Here, we show that mammary tumors have increased CGRP⁺ sensory innervation. Using our novel microfluidic Device for Cancer cell-Axon Interaction Testing (DACIT), we demonstrate that the presence of axons strongly inhibits ECM-degrading ability of cancer cells. The sensory neuron secretome suppresses assembly and function of invadopodia, which are cancer cell protrusions controlling ECM degradation, and essential for intravasation and metastasis. We identify calcitonin gene-related peptide (CGRP) as the key component of the sensory neuron secretome responsible for the inhibitory effect. CGRP signaling occurs through the CRLR/RAMP1 receptor complex expressed by breast cancer cells, inducing a rapid increase in intracellular cAMP levels in breast cancer cells, followed by an increase in RhoC activity and suppression of invadopodia and ECM degradation. Loss of RAMP1 function enhances 3D spheroid invasion, cancer cell motility in vivo and significantly increases the number and the size of lung metastatic foci. Consistently, in silico analyses of both mouse and human RNASeq data point to a link between increasingly invasive subtypes with a gradual decrease in expression of RAMP1 and CRLR. To validate in silico findings, we compare RAMP1 expression in the patient breast tumors with adjacent normal tissues, confirming the invasive breast tumors have reduced levels of RAMP1. Together, our findings identify a protective role for the paracrine CGRP signaling in limiting breast cancer invasion and metastasis. We also demonstrate how cancer cells circumvent CGRP inhibition by suppressing RAMP1 expression, highlighting CGRP-RAMP1-cAMP axis as a potential therapeutic target in breast cancer.

DOI: https://doi.org/10.64898/2026.04.17.719233
Front Immunol. 2026 ;17 1806570

The hallmarks of neuro-immune reprogramming in cancer.

Jhommara Bautista, Andrés López-Cortés.

  Cancer immunity is commonly interpreted through tumor-centric and immune-intrinsic frameworks centered on antigenicity, immune checkpoint signaling, stromal architecture, and local immunosuppression within the tumor microenvironment. Although these models explain major determinants of immune surveillance and therapeutic response, they do not fully account for the marked heterogeneity in antitumor immunity observed across tumor types and among patients with apparently similar immunological features. Emerging evidence indicates that immune competence is also shaped by host-level regulatory systems, particularly neural and neuroendocrine pathways. Here, we propose the hallmarks of neuro-immune reprogramming in cancer as a conceptual framework to organize recurrent and analytically distinguishable modes through which neural circuits interact with tumor-, stromal-, and immune-intrinsic processes to influence antitumor immunity across its initiation, tissue access, metabolic sustainability, temporal coordination, and persistence. These hallmarks include neural calibration of innate immune set points, neurogenic control of antigen presentation and immune priming, neural gating of immune cell trafficking and tissue access, neuroendocrine constraint of immune metabolic fitness, circadian-neural orchestration of immune timing, neural imprinting of durable immunosuppressive bias, and neuro-immune-tumor circuit reinforcement. Importantly, the evidentiary maturity supporting these hallmarks is not uniform: some are supported by direct cancer-relevant mechanistic studies, whereas others currently remain best understood as cross-disciplinary inferences or testable conceptual extensions. Together, this framework positions neuro-immune regulation as an under integrated systems-level determinant of immune heterogeneity, therapeutic responsiveness, and resistance in cancer, and provides a foundation for mechanistic investigation, biomarker development, and neural-informed immunotherapeutic strategies.

Keywords:  cancer immunity; circadian-neural orchestation; hallmarks; immunotherapy; neuro-immune reprogramming

DOI:  https://doi.org/10.3389/fimmu.2026.1806570
Neuron. 2026 May 07. pii: S0896-6273(26)00269-2. [Epub ahead of print]

A peritumoral microenvironment engaged by Reg-EXTL3 axis fosters nerve-cancer interactions in pancreatic ductal adenocarcinoma.

Shan Zhang, Fang-Yuan Dong, Shuqi Cai, Bin Zhou, Luju Jiang, Li-Peng Hu, Yu-Heng Zhu, Hui Li, Xiao-Mei Yang, Zhiwei Cai, Lin-Li Yao, Hao Wang, Hong-Fei Yao, Jun Li, Qing Li, Lei Zhu, Qin Yang, Li-Min Liu, Yan-Qiu Yu, Jun-Feng Zhang, Rong Hua, Xue-Li Zhang, Helen He Zhu, Ningning Niu, Jing Xue, Chongyi Jiang, Yong-Wei Sun, Qingjian Han, Dong-Xue Li, De-Jun Liu, Zhi-Gang Zhang, Shu-Heng Jiang.

  Tumor innervation (TIN) and perineural invasion (PNI) are well-established pathological features of pancreatic ductal adenocarcinoma (PDAC) that drive its aggressiveness and associated pain. Here, we reveal that regenerating islet-derived (Reg) proteins, secreted by peritumoral exocrine acinar cells, facilitate TIN and PNI through two paracrine mechanisms. In PDAC cells, Reg proteins drive cancer invasiveness along nerves via autocrine transforming growth factor β (TGF-β) signaling. In neurons, Reg proteins are neurotrophic and potentiate neuronal excitability, resulting in hyperinnervation and pain. Interleukin-22, primarily produced by CD4+ T cells, triggers Reg expression. Exostosin-like glycosyltransferase 3 (EXTL3) is the functional receptor for Reg proteins in both cell types. Genetic silencing of Reg or EXTL3 reduces TIN, nerve-cancer proximity, PDAC progression, and pain behavior in mice. Clinically, the Reg-EXTL3-TGF-β axis correlates with increased TIN and PNI severity, poor prognosis, and greater pain. Thus, targeting the Reg-EXTL3 axis may be an attractive strategy for mitigating neural-associated adverse consequences in PDAC.

Keywords:  cancer neuroscience; nerve dependence; neural invasion; neural remodeling

DOI:  https://doi.org/10.1016/j.neuron.2026.03.039
Front Oncol. 2026 ;16 1801005

Perineural invasion in solid tumors: biological foundations and the emerging integration of machine learning and artificial intelligence.

Hisham F Bahmad, Yasamin Mirzabeigi, Youssef K Elajami, Wassim Abou-Kheir, Navya Nair.

  Perineural invasion (PNI) represents a distinct route of cancer spread in many solid tumors. Its presence correlates with aggressive tumor behavior, local recurrence, neuropathic symptoms, and reduced survival across selected tumor types, including pancreatic, prostate, head and neck, colorectal, and gynecologic malignancies, among others. Despite its prognostic value, PNI remains inconsistently detected and reported, and incompletely integrated into the College of American Pathologists (CAP) cancer protocols and clinical decision-making. Over the last decade, advances in tumor-nerve biology have reframed PNI as an active, bidirectional phenomenon driven by molecular crosstalk between cancer cells, Schwann cells, neurons, and the surrounding tumor microenvironment (TME). Parallel advances in digital pathology, machine learning (ML), and artificial intelligence (AI) have opened new opportunities to standardize PNI detection and quantify its extent. This review provides a synopsis of current knowledge on the biological mechanisms and clinical relevance of PNI in solid tumors, with the emerging integration and application of ML- and AI-assisted approaches in histopathology and molecular profiling to advance detection and potential therapeutic targeting of PNI.

Keywords:  artificial intelligence; digital pathology; machine learning; perineural invasion; review; solid tumors

DOI:  https://doi.org/10.3389/fonc.2026.1801005
Biochem Biophys Rep. 2026 Jun;46 102611

The role of γ-aminobutyric acid and its receptor in metabolic reprogramming and tumor progression.

Yujie Wang, Junzhao Shao, Ming Wang, Zhenlong Sun, Nan Wang, Wei Li, Hong Luo.

  Neurotransmitters play fundamental regulatory roles within the central nervous system (CNS), where they modulate neuronal signaling and maintain neural network homeostasis. Beyond their classical functions in the CNS, these signaling molecules can act on other organs throughout the body via vagus nerve terminals, mediating crosstalk between the nervous system and peripheral tissues. Notably, such neurotransmitter-mediated interorgan communication has been implicated in driving metabolic reprogramming, a key adaptive process that can promote tumor initiation and progression. Among the diverse neurotransmitters involved, γ-aminobutyric acid (GABA) has garnered increasing attention, as it exhibits elevated levels in various types of tumors. Accordingly, this review focuses on elucidating the mechanisms of GABA synthesis and secretion, while systematically investigating the role of GABA and its receptors in metabolic reprogramming and the regulation of the tumor immune microenvironment. Collectively, this work aims to unravel the multifaceted contributions of GABA to oncogenesis and thereby to offer novel therapeutic targets for cancer treatment.

Keywords:  Cancer; GABA; GABA receptors; Metabolic reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbrep.2026.102611
bioRxiv. 2026 Apr 23. pii: 2026.04.21.719930. [Epub ahead of print]

Pancreatic cancer fibrosis activates protumorigenic Schwann cells through a nuclear mechanosensing mechanism.

Pavel Stupakov, Golbahar Sadatrezaei, Ines Velazquez Quesada, Lillian A Boe, Chun-Hao Chen, Francesca Gaino, Efsevia Vakiani, Ihsan Ekin Demir, Boris Reva, Bojana Gligorijevic, Richard J Wong, Sylvie Deborde.

Background: Fibrosis and tumor innervation are two features of the tumor microenvironment (TME) that contribute directly to the lethality of pancreatic ductal adenocarcinoma (PDAC), but their potential interactions have not been explored. Moreover, although it is known that activated Schwann cells (SCs) stimulate cancer cell invasion, it remains unclear how SCs are activated.
Objective: We determined how SCs are activated in the pancreatic fibrotic microenvironment.
Design: The correlation between physical features of the microenvironment and SC activation was assessed in human patient samples and in mice by SC c-Jun phosphorylation monitoring, atomic force microscopy and multiphoton live imaging. Several in vitro models in which forces were applied to SCs expressing a reporter for c-Jun phosphorylation and RNA-Seq analysis were used to decipher the cellular and molecular mechanisms of SC activation.
Results: Nerves surrounded by stiff stroma present higher SC activation. Intravital imaging shows a matrix dependent SC activation. Mechanical forces on SCs induce c-Jun phosphorylation in SCs in a non-canonical manner that involves a nuclear sensing machinery with the proinflammatory enzyme Phospholipase A2.
Conclusion: Fibrosis enhances the protumorigenic impact of innervation by activating SCs via a mechanism in which nuclear compression triggers non-canonical activation of the AP-1 transcription factor complex. Pancreatic fibrosis alone, without cancer cells, is sufficient to activate SCs, suggesting this mechanism may be common across non-malignant pancreatic diseases. Notably, SCs are more sensitive to mechanical activation than PDAC cells. These findings reveal TME interactions that may guide future microenvironment-targeted PDAC therapies.
What is already known on this topic: The pancreatic cancer tumor microenvironment is highly innervated and fibrotic, two components of the tumor microenvironment that regulate tumorigenesis. How they impact each other is unknown. Schwann cells have emerged as a significant protumorigenic player, but the triggers of Schwann cell activation remain undefined.
What this study adds: We establish that fibrosis induces Schwann cell activation and characterize the mechanism by which it occurs. We uncovered a mechanical mode of action that deforms nuclear membrane and activates c-Jun in Schwann cells, which contradicts the traditional view of c-Jun activation through a stimulus detected at the plasma membrane.
How this study might affect research practice or policy: This study provides a better understanding of the biology of pancreatic ductal adenocarcinoma and supports the development of novel precision therapies that target the fibrotic microenvironment to impact the protumorigenic effect of tumor innervation.

DOI: https://doi.org/10.64898/2026.04.21.719930
Nature. 2026 May 05.

Editorial Expression of Concern: Nociceptive neurons promote gastric tumour progression via a CGRP-RAMP1 axis.

Xiaofei Zhi, Feijing Wu, Jin Qian, Yosuke Ochiai, Guodong Lian, Ermanno Malagola, Biyun Zheng, Ruhong Tu, Yi Zeng, Hiroki Kobayashi, Zhangchuan Xia, Ruizhi Wang, Yueqing Peng, Qiongyu Shi, Duan Chen, Sandra W Ryeom, Timothy C Wang.

DOI: https://doi.org/10.1038/s41586-026-10594-5
Endocrine. 2026 May 04. pii: 172. [Epub ahead of print]91(1):

Tumor size and vascular and perineural invasion predict mesenteric involvement in small-intestinal neuroendocrine tumors.

Murad Ali, Alessandro Gambella, Alessandro Vanoli, Chandra Bortolotto, Edoardo D'Este, Filippo Checchin, Manuela Albertelli, Diego Ferone, Virginia Sambuceti, Giuseppe Cittadini, Atta Ur Rehman, Federica Grillo.



Keywords:  Small-intestinal neuroendocrine tumor; collagen quantification; mesenteric involvement; perineural invasion; primary tumor size; vascular invasion

DOI:  https://doi.org/10.1007/s12020-026-04636-1
Nat Commun. 2026 May 08.

Disrupting sympathetic nerve-tumor crosstalk via biomimetic nanovesicles to augment chemotherapy efficacy under chronic stress.

Jingjie Liu, Jiaqi Qin, Wenxia Zheng, Xiaojuan Wang, Zhaohan Wei, Zixiang Xie, Tingwei Yan, Xin Li, Ziqiao Ding, Haojie Liu, Zhiheng Cai, Shanmiao Gou, Xiangliang Yang, Tuying Yong, Lu Gan.

Chronic stress significantly impacts cancer progression by activating the sympathetic nervous system, leading to increased tumor growth, metastasis, and resistance to chemotherapy. To address these challenges, we develop biomimetic hybrid nanovesicles (Pro@hNVs) by fusing M1 macrophage-derived vesicles with pH-sensitive liposomes (hNVs) to encapsulate the β-adrenergic receptor (ADRB) blocker propranolol (Pro). Leveraging the tumor-targeting properties of M1 macrophage-derived vesicles and their matrix metalloproteinase-mediated degradation of tumor extracellular matrix, Pro@hNVs effectively accumulate and deeply penetrate tumor tissues, followed by the release of Pro in response to the acidic tumor microenvironment. Pro subsequently inhibits the sympathetic nerve-cancer cell crosstalk by blocking ADRB2 signaling. Meanwhile, Pro@hNVs effectively reprogram adrenergic signal-induced M2-like tumor-associated macrophages (TAMs) into the M1 phenotype through the released Pro and hNVs, thereby amplifying TNF-mediated neurotoxicity and effectively disrupting sympathetic nerve-macrophage crosstalk. This dual-action mechanism of Pro@hNVs significantly inhibits the sympathetic nerve function promoted by gemcitabine, resulting in the improved chemotherapy efficacy and enhanced antitumor immune response under chronic stress. These findings highlight the potential of Pro@hNVs as a promising strategy to enhance chemotherapy outcomes in cancer patients experiencing chronic stress, offering a viable therapeutic avenue for overcoming treatment resistance.

DOI: https://doi.org/10.1038/s41467-026-72847-1
Cell Rep. 2026 May 05. pii: S2211-1247(26)00418-3. [Epub ahead of print]45(5): 117340

Pan-cancer neurotransmitter receptor alterations define neuroregulatory subtypes with prognostic significance.

Shangyi Luo, Shupei Qiao, Li Liu, Zhuang Xiong, Lei Guo, Xin Hao, Xue Zhang, Yajing Zhang.

  Cancer neuroscience highlights the critical role of neural signaling in tumors, yet a pan-cancer understanding of neuroregulatory dysregulation is lacking. We systematically characterized 130 neurotransmitter receptor (NTR) genes across 9,125 tumors from 33 cancer types. Our analysis revealed heterogeneous NTR mutations, with 17 cancer types showing elevated rates. Notably, amplification of the muscarinic receptor gene CHRM2 exhibited mutual exclusivity with the clinically actionable gene ERBB2, suggesting its potential as a therapeutic target. NTR expression was widely dysregulated and associated with altered DNA methylation, microRNA (miRNA) expression, and patient prognosis. Unsupervised clustering identified five recurrent neuroregulatory subtypes with distinct clinical and molecular features across cancers. Using low-grade glioma and liver cancer as examples, we validated that the S4 and S1 subtypes were consistently correlated with aggressive disease and poor outcomes in these two cancers, respectively. This study establishes a foundational framework for advancing cancer neuroscience and targeting neuroregulatory signaling in cancer therapy.

Keywords:  CHRM2; CP: Cancer; CP: Neuroscience; ERBB2; cancer neuroscience; liver cancer; low-grade glioma; multi-omics analysis; neuroregulatory subtypes; neurotransmitter receptor; pan-cancer

DOI:  https://doi.org/10.1016/j.celrep.2026.117340
Biomed Pharmacother. 2026 May 06. pii: S0753-3322(26)00508-1. [Epub ahead of print]199 119472

Advances in mechanisms and treatments of brain metastases.

Weijian Zhou, Ziwei Zhang, Jiayan Wang, Siyuan Chen, Xin Hu, Manni Wang.

  Statistics indicate that brain metastases occur in nearly 30% of patients with solid tumors, with lung cancer, breast cancer, and melanoma being the three most common primary sources. Brain metastasis is characterized by the co-evolution of tumor cells co-evolve with the brain microenvironment, inducing changes in the phenotype of brain stromal cells that facilitate the colonization, survival, and growth of tumors. The prognosis for brain metastases remains poor, with 2-year and 5-year survival rates for patients diagnosed with brain metastases of 8.1% and 2.4%, respectively. Notably, more than half of brain metastases patients die from neurological diseases. Current treatment options for brain metastases include radiotherapy, neurosurgery, systemic chemotherapy, targeted therapy, and immunotherapy, which are often used in combination to improve therapeutic outcomes. In recent years, the use of nanomaterials for brain metastases treatments has been progressively developed to enhance the efficiency and precision of drug delivery. In the future, with a deeper understanding of the mechanisms underlying brain metastases and further development of treatment strategies, patient outcomes are expected to improve. This review, summarizes the current understanding of brain metastasis mechanisms and therapeutic approaches, and outlines an outlook on future research directions in the field.

Keywords:  Brain metastases; Immunotherapy; Nanomaterials; Neurosurgery; Radiotherapy; Targeted therapy

DOI:  https://doi.org/10.1016/j.biopha.2026.119472