bims-netuvo 2026-03-22 papers

Int Immunopharmacol. 2026 Mar 17. pii: S1567-5769(26)00355-3. [Epub ahead of print]177 116510

Targeting tumor-associated sympathetic nerves orchestrates tertiary lymphoid structures to enhance PD-1/PD-L1 blockade efficacy.

Zhiqin Zeng, Yedi Huang, Jiaying Shen, Wei Wu, Yangxin Hu, Xiaoming Wang, Rui Peng, Mengya Zhao, Chupeng Hu, Cheng Pan.

Tumor-innervating peripheral nerves have been implicated in tumor initiation and progression; however, the contribution of sympathetic nerve infiltration to gastric cancer (GC) prognosis and immunotherapy response remains unclear. Here, we demonstrate that high TH+ fiber density in GC is associated with poorer survival and reduced responsiveness to immune checkpoint blockade (ICB) response. Sympathetic innervation inversely correlated with CXCL13+ CD8+ T-cell infiltration and tertiary lymphoid structure (TLS) abundance. In murine models, chemical sympathectomy using 6-OHDA suppressed tumor growth, enhanced CXCL13+ CD8+ T-cell effector function, promoted TLS formation, and reduced lung metastasis. Mechanistically, sympathetic neural activity restrains CD8+ T-cell-mediated anti-tumor immunity via β-adrenergic signaling. Therapeutically, the combination of the β-blocker Atenolol and αPD-L1 therapy synergistically enhanced anti-tumor immunity, highlighting sympathetic signaling as therapeutic targets to potentiate immunotherapy. Pan-cancer analyses further revealed negative associations between TH expression, immune activation signatures, and αPD-1 therapy benefit. Collectively, our findings demonstrate that sympathetic nerve infiltration constrains anti-tumor immunity and limits the efficacy of αPD-L1 therapy in GC. Targeting adrenergic signaling to relieve this immunosuppressive constraint-by promoting CXCL13+ CD8+ T cells and TLS formation-may improve immunotherapy outcomes in GC and potentially other malignancies.

Keywords: CXCL13(+) CD8(+) T-cell; Gastric cancer; Sympathetic nerves; Tertiary lymphoid structure; αPD-L1 therapy

DOI: https://doi.org/10.1016/j.intimp.2026.116510

Cancer Metastasis Rev. 2026 Mar 17. pii: 18. [Epub ahead of print]45(2):

Neuro-tumor interactions in peripheral tumors.

Xueshiyu Ma, Peixuan Ji, Jiahao Zheng, Shuqi Cai, Kan Xu, Yongwei Sun, Dejun Liu.

The nervous system is now recognized as a pivotal regulator of cancer, marking a paradigm shift that recasts nerves from passive bystanders to active drivers within the tumor microenvironment (TME). This review defines the "neural niche," differentiating passive perineural invasion (PNI) from active tumor innervation. We examine how sympathetic signaling drives an "angio-metabolic switch" and immune evasion, whereas parasympathetic inputs exert context-dependent control over stemness and inflammation. We also highlight the underappreciated role of sensory neurons in promoting T-cell exhaustion via neuropeptides like calcitonin gene-related peptide (CGRP). Finally, we assess therapeutic strategies targeting neural dependence-from repurposing β-blockers to deploying nanotechnologies. Targeting neuro-tumor crosstalk offers a promising strategy to overcome therapeutic resistance and restore anti-tumor immunity.

Keywords: Nerve dependence; Neural invasion; Neuroscience; Neurotransmitter antagonists and tumor innervation

DOI: https://doi.org/10.1007/s10555-026-10321-6

Biochim Biophys Acta Rev Cancer. 2026 Mar 12. pii: S0304-419X(26)00047-8. [Epub ahead of print]1881(3): 189575

Neuro-tumor-immune crosstalk in pancreatic cancer: Mechanisms and therapeutic insights.

Jianguo Jin, Bin He, Xiang Wang, Yuqiang Zhang, Huiming You, Sirui Mo, Duancheng Guo, Saimeng Shi.

The nervous system functions as a central regulatory network that maintains physiological homeostasis through the coordinated actions of the central and peripheral nervous systems. The emergence of cancer neuroscience has unveiled novel mechanisms underlying bidirectional regulation among the nervous system, tumor cells, and the immune system. This review focuses on pancreatic cancer, often referred to as the "king of cancers," a malignancy characterized by aggressive behavior, early perineural invasion, and dismal prognosis. We systematically analyze the interactions within the neuro-tumor-immune microenvironment. On one hand, the peripheral and central nervous systems promote neurotropic migration of cancer cells and the formation of a tumor immunosuppressive microenvironment through neurotransmitters, neurotrophic factors, and synaptic remodeling. On the other hand, cancer cells and the immune microenvironment reshape neural structures, exacerbating immune evasion and malignant progression. Furthermore, this review integrates fundamental mechanisms with translational and clinical research, and proposes neuroscience-guided precision therapeutic strategies, including the development of neural invasion-related biomarkers and the targeting of key nodes within neuro-tumor-immune interactions. Together, these approaches add a new dimension to overcoming therapeutic bottlenecks in pancreatic cancer and facilitate the translation of mechanistic insights into clinical applications.

Keywords: Cancer neuroscience; Neuro-tumor-immune crosstalk; Pancreatic cancer; Perineural invasion; Tumor microenvironment

DOI: https://doi.org/10.1016/j.bbcan.2026.189575

JHEP Rep. 2026 Feb 05. pii: S2589-5559(26)00041-8. [Epub ahead of print]8(4): 101770

Perineural invasion is a prognostic factor in cholangiocarcinoma, regardless of anatomical location: A systematic review and meta-analysis.

Sefora Conti, Natalia S Tissera, Florian Castet, Míriam Basagaña-Farrés, María Teresa Salcedo, Elizabeth Pando, Cristina Dopazo, Lorenzo Caritá, Anthony Turpin, Víctor Navarro Garcés, Guillermo Villacampa, Teresa Macarulla, Tian V Tian.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA), a heterogeneous malignancy that includes intrahepatic (iCCA), perihilar (pCCA), and distal (dCCA) subtypes, often exhibits perineural invasion (PNI). Despite PNI being associated with postoperative recurrence, evidence on its prognostic impact remains inconsistent. To clarify this, we conducted a systematic review and meta-analysis.
METHODS: A comprehensive literature search was conducted across the Medline-PubMed, Embase, and Web of Science databases from their inception through February 27, 2025. We included studies involving patients diagnosed with CCA who underwent surgery and for whom PNI data were available. The primary outcomes were overall survival (OS) and disease-free survival (DFS), extracted from both univariable and multivariable analyses. The study is registered in PROSPERO (CRD42024575458).
RESULTS: Of 1,555 articles screened, 64 retrospective studies comprising 15,543 patients were included. In the univariable analysis, the pooled hazard ratio (HR) for OS from 34 studies (6,084 patients) was 1.92 (95% CI 1.67-2.21, I2 = 59.6%). Multivariable-adjusted analysis of 42 studies (10,335 patients) showed an HR of 1.68 (95% CI 1.47-1.90, I2 = 47.9%) for patients with PNI. For DFS, the pooled univariable HR in 6,110 patients was 1.70 (95% CI 1.46-1.98, I2 = 52.3%), and the multivariable HR was 1.62 (95% CI 1.37-1.92, I2 = 70.5%)). Prognostic consistency was observed across anatomical subgroups. Univariable OS HRs were 2.14 for iCCA, 1.69 for pCCA, and 1.66 for dCCA. Corresponding multivariable HRs were 1.74, 1.60, and 1.66, respectively.
CONCLUSIONS: PNI is a prognostic factor for both DFS and OS in CCA, regardless of anatomical location. Further research is needed to elucidate its biological mechanisms and potential therapeutic implications.
IMPACT AND IMPLICATIONS: This comprehensive review and meta-analysis confirms that perineural invasion (PNI) predicts poorer overall and disease-free survival in cholangiocarcinoma, independent of tumor location. These results highlight the potential of PNI as a reliable histopathological marker to stratify postoperative risk and inform patient management. While most evidence is retrospective and smaller studies may overstate the effect, the consistent findings emphasize the need for large, multicenter prospective studies with standardized pathological assessment. Such efforts could facilitate the integration of PNI into prognostic models and support more individualized treatment strategies for patients with cholangiocarcinoma.

Keywords: anatomic location; cholangiocarcinoma; disease-free survival; overall survival; perineural invasion; prognostic factor

DOI: https://doi.org/10.1016/j.jhepr.2026.101770

Cancer Biol Ther. 2026 Dec 31. 27(1): 2644788

Deguelin inhibits perineural invasion in esophageal squamous cell carcinoma via targeting BDNF/TrkB axis.

Qiying Wei, Liuyang Bai, Liangying Yan, Zhongyu Wang, Rongyao Jin, Bingjie Li, Wenbo Cao, Saijun Mo.

BACKGROUND: Perineural invasion (PNI) represents a uniquely distinctive pathway for tumor metastasis, but its underlying molecular mechanisms and therapy remain unclear.
METHODS: Bioinformatics analysis and transcriptomic sequencing were first employed to investigate the involvement of the BDNF/TrkB axis in the ESCC PNI, which was validated with ESCC cells co-cultured with a dorsal root ganglia system (ESCC/DRG model), a mouse PNI model, and ESCC tissues, mainly using microscopic imaging, IVIS Spectrum in vivo imaging, Western blot (WB), and immunohistochemistry (IHC). Additionally, transcriptomic sequencing and WB were conducted to analyze the downstream molecular mechanisms of the BDNF/TrkB axis. Similar experiments were applied to investigate the role of Deguelin in ESCC PNI. Deguelin's interaction with BDNF was assessed using computational docking, pull-down assays, cellular thermal shift assays, surface plasmon resonance (SPR) and WB. Its inhibitory effects on the ESCC PNI were further evaluated through rescue experiments, where BDNF overexpression was used to counteract Deguelin's activity.
RESULTS: The BDNF/TrkB axis is closely associated with the PNI in ESCC. This pathway plays a pivotal role in driving PNI progression via Akt signaling. Deguelin was identified as an effective inhibitor of PNI in ESCC. Mechanistically, BDNF was revealed to be a key binding target of Deguelin, which disrupts PNI development by modulating the BDNF/TrkB/Akt axis. Notably, overexpression of BDNF can counteract Deguelin's inhibitory effects on ESCC growth and PNI progression.
CONCLUSION: The BDNF/TrkB axis promotes the progression of ESCC PNI, and Deguelin inhibits ESCC PNI by targeting this axis, enhancing the understanding of PNI's molecular mechanisms and offering new therapeutic options.

Keywords: BDNF; Deguelin; PNI; TrkB; esophageal squamous cell carcinoma

DOI: https://doi.org/10.1080/15384047.2026.2644788

Mol Oncol. 2026 Mar 18.

Deciphering transcriptional plasticity in pancreatic ductal adenocarcinoma reveals alterations in sensory neuron innervation.

Elena Genova, Michele Montrone, Uday Rangaswamy, Francesco Diversi, Irene Schiavo, Denise Ferrarini, Roberta Di Florio, Irene Longo, Michele Coscia, Nicola Zamboni, Giorgia Demontis, Lisa Veghini, Vincenzo Corbo, Remo Sanges, Paul Heppenstall.

Neuronal innervation of the pancreas has historically been characterized using marker-based classification and physiological studies, but its transcriptomic landscape remains only partially explored. A detailed molecular profile of pancreatic sensory neurons could provide insights into their role in health and disease, particularly in pancreatic ductal adenocarcinoma (PDAC), where neural remodeling influences tumor progression and pain signaling. Wild-type and PDAC mice were injected with the retrotracer Fast Blue into pancreatic or cancerous tissue. Dorsal root ganglia were dissociated, and Fast Blue-positive sensory neurons were isolated, lysed, and analyzed using single-cell RNA sequencing. Data were validated using immunofluorescence, organoid cultures and qPCR. We performed transcriptomic profiling of sensory neurons innervating the pancreatic head and tail under normal and cancer conditions. Our analysis identified neurofilament-containing neurons as the predominant sensory subtype in both contexts, while non-peptidergic neurons were underrepresented in tumor-associated innervation. Differential gene expression analysis revealed a unique subset of genes upregulated in sensory neurons innervating pancreatic tumors, many linked to mitochondrial activity. Further validation also revealed the presence of transcripts transferred via extracellular vesicles (including the Pdx1-CreERT2 transgene from the KPC mouse model), suggesting a novel mechanism of tumor-neuron interaction. Our findings provide a detailed characterization of pancreatic and pancreatic ductal adenocarcinoma sensory innervation. We identified tumor-derived RNA within sensory neurons in the PDAC mouse model, suggesting an extracellular vesicle-mediated RNA transfer mechanism that may remodel sensory signaling and open new prospects for diagnostic and therapeutic innovation in PDAC. Impact statement Transcriptomic profiling of pancreatic sensory neurons reveals shifts in neuronal populations, tumor-specific mitochondrial gene upregulation, and potential extracellular vesicle-mediated transcript transfer. Circulating tumor transcripts in KPC mice provide a reference for pancreatic innervation, tumor-nerve interactions, and therapeutic targets.

Keywords: pancreas; pancreatic ductal adenocarcinoma; sensory neurons; single‐cell RNA sequencing; tumor microenvironment

DOI: https://doi.org/10.1002/1878-0261.70233