bims-netuvo 2026-04-19 papers

Cell. 2026 Apr 16. pii: S0092-8674(26)00285-0. [Epub ahead of print]189(8): 2464-2489

Cancer neuroscience: The past, the present, and the road ahead.

Both the nervous system and cancer-intrinsic neural features can govern cancer initiation, growth, progression, metastasis, and treatment resistance, while cancer can likewise influence the nervous system, promoting neural reprogramming and neuropsychiatric symptoms that worsen patient outcomes. The field of cancer neuroscience seeks to unravel this complex neuro-cancer crosstalk and holds the promise to develop neuroscience-instructed cancer therapies that improve disease control and quality of life. Here, we summarize the key discoveries of neuro-cancer crosstalk to date, including neuron-to-cancer synapses and paracrine and neuro-immuno-oncological interactions, and then explore emerging topics such as downstream effects on cancer cell pathophysiology, circadian influences, brain-body-cancer communication, and neural regulation of the metastatic cascade and the tumor microenvironment. Finally, we distill overarching principles, highlight relevant ongoing research, and outline conclusions to guide the development of cancer neuroscience, proposing hypotheses for future experimental validation.

DOI: https://doi.org/10.1016/j.cell.2026.03.018

Cancers (Basel). 2026 Mar 25. pii: 1063. [Epub ahead of print]18(7):

Neural Innervation of Tumors: Mechanisms, Hallmarks, and Therapeutic Opportunities.

Shamir Cassim, Christopher Montemagno.

Background/Objectives: Increasing evidence indicates that tumors interact functionally with the nervous system. Rather than being passively innervated, many cancers establish bidirectional communication with neurons, suggesting that neural activity may represent an additional regulatory layer of tumor biology. This review aims to synthesize current knowledge on the mechanisms and consequences of tumor innervation and to discuss its implications for cancer progression and therapy. Methods: We performed a narrative synthesis of recent experimental and translational studies (2015-2026), identified through PubMed and major peer-reviewed biomedical journals. The literature was analyzed to identify key mechanisms of neural influence on tumor biology, including axonogenesis, pseudo-synaptic communication, neurotransmitter signaling, and metabolic coupling. Results: Emerging evidence indicates that neural inputs can regulate multiple hallmarks of cancer, including proliferation, invasion, angiogenesis, metabolic plasticity, and immune evasion. Tumors can actively recruit nerve fibers through axonogenic signals and establish specialized neuron-cancer interfaces that enable activity-dependent oncogenic signaling. In addition, neuronal interactions can influence tumor metabolism and therapeutic resistance through mechanisms such as mitochondrial transfer and neurotransmitter-driven signaling pathways. Conclusions: Tumor innervation represents an important and increasingly recognized dimension of cancer biology. Understanding how neural circuits interact with tumor cells and the surrounding microenvironment may reveal new biomarkers and therapeutic strategies aimed at disrupting tumor-neuron communication.

Keywords: cancer neuroscience; cancer progression; glioma; neural regulation of cancer; neuron–tumor interactions; neurotransmitter signaling; tumor innervation; tumor microenvironment

DOI: https://doi.org/10.3390/cancers18071063

J Biochem. 2026 Apr 13. pii: mvag028. [Epub ahead of print]

Dynamic Changes of the Sympathetic Nervous System in the Bone Marrow in Myeloid Leukemia.

Sayumi Okigawa, Hibiki Inafuku, Ayuna Hattori, Takahiro Ito.

Chronic myeloid leukemia (CML) is a hematologic malignancy originating from hematopoietic stem cells with the fusion oncogene BCR-ABL1 on the Philadelphia chromosome, which drives the abnormal proliferation of leukemic blast cells within the bone marrow microenvironment. While previous research has primarily focused on the hematopoietic compartment, the functional contribution of the bone marrow microenvironment to the CML pathology remains understudied. We investigated the changes in the peripheral nervous system in the bone marrow with myeloid leukemia via immunofluorescence staining of tyrosine hydroxylase (TH) and calcitonin gene-related peptide (CGRP) antibodies in mouse with NUP98-HOXA9- and BCR-ABL1-expressing myeloid leukemia. We found that the TH-positive fibers were significantly reduced, while no overt changes were observed in CGRP-positive nerves in the bone marrow. The reduction in TH-positive nerve cells was also evident in the spleen. Human patient gene expression data suggested that the levels of sympathetic nerve receptor expression change during the blastic transformation of human CML. Our findings indicate that the sympathetic nervous system regulates the pathogenesis of myeloid leukemia and could play a crucial role in the disease progression of myeloid leukemia.

Keywords: bone marrow; microenvironment; myeloid leukemia; peripheral nervous system; sympathetic nervous system

DOI: https://doi.org/10.1093/jb/mvag028

Int Immunopharmacol. 2026 Apr 10. pii: S1567-5769(26)00481-9. [Epub ahead of print]179 116636

Perineural invasion: A neuroimmune axis mediating immunotherapy resistance across malignancies.

Jingchong Guo, Zijian Hu, Longren Wu, Lehuang Liu, Zhenjie Li, Linmin Xiong, Dongliang Yu.

Perineural invasion has traditionally been regarded as a distinct anatomical route of tumor spread, following direct invasion, hematogenous dissemination, and lymphatic metastasis. However, accumulating evidence indicates that perineural invasion represents more than a passive conduit for cancer dissemination. Perineural invasion is frequently observed in aggressive malignancies, including head and neck squamous cell carcinoma, pancreatic ductal adenocarcinoma, gastric cancer, melanoma, prostate cancer and breast cancer, and is strongly associated with tumor progression, immune evasion, therapeutic resistance, and poor clinical outcomes. Although immune checkpoint blockade targeting the PD-1/PD-L1 axis has achieved substantial clinical success across multiple cancer types, resistance to immunotherapy remains a major unresolved challenge. Recent studies reveal that perineural invasion and cancer-induced nerve injury actively reshape the tumor immune microenvironment through sustained neuro-immune crosstalk, thereby promoting immune suppression, T-cell dysfunction, and resistance to immunotherapy. Notably, emerging mechanistic insights from pancreatic ductal adenocarcinoma and cutaneous squamous cell carcinoma have provided key evidence supporting the role of PNI-driven neuro-immune interactions in shaping immunotherapy resistance. In this review, we synthesize current evidence delineating the molecular and cellular mechanisms underlying PNI-driven immune remodeling, with a particular focus on neurotrophic signaling, chemokine-mediated immune exclusion, exosome-dependent communication, and chronic neuroinflammatory responses. By redefining perineural invasion as a dynamic neuro-immune regulatory axis, this review provides a conceptual framework for understanding PNI-associated immune escape and highlights emerging therapeutic strategies aimed at overcoming immunotherapy resistance.

Keywords: Cutaneous squamous cell carcinoma; Immunotherapy; Pancreatic ductal adenocarcinoma; Perineural invasion; cancer-induced neural injury

DOI: https://doi.org/10.1016/j.intimp.2026.116636

JHEP Rep. 2026 Feb 28. pii: S2589-5559(26)00078-9. [Epub ahead of print]8(5): 101807

Spatial profiling defines three immunophenotypes and a perineural invasion-associated immune-evasion niche in gallbladder cancer.

Xing He, Xin Yang, Sicheng Xu, Xinxin He, Gui He, Huilin Ye, Qixian Zhou, Junkai Ren, Liqiang Liu, Jie Wang, Yaorong Peng, Zhenyu Zhou, Wenbin Li.

BACKGROUND & AIMS: Gallbladder cancer (GBC) has a high risk of postoperative recurrence, and immunotherapy-based adjuvant approaches remain unstandardised. We aimed to define spatial immunophenotypes in GBC and evaluate their associations with clinical outcomes and immune-evasion mechanisms.
METHODS: We used multiplex immunohistochemistry to quantify 16 immune-cell subsets across the tumour core, tumour margin and peritumour regions in 86 treatment-naïve GBCs, and integrated nerve bundle-centred spatial analysis with transcriptomic profiling (n = 9) to investigate perineural invasion (PNI)-associated immune-evasion mechanisms.
RESULTS: Unsupervised clustering and a CD8/α-SMA dual-marker approach defined three spatial immunophenotypes: immune-inflamed, immune-excluded, and immune-desert. The immune-inflamed phenotype featured high intratumoural immune infiltration with elevated PD-L1 expression (median combined positive score: 13.85 vs. 0.41 vs. 0.25, p <0.001), was associated with better prognosis (overall survival [OS]: hazard ratio [HR] 0.25, 95% CI 0.12-0.54, p <0.001; recurrence-free survival [RFS]: HR 0.41, 95% CI 0.21-0.79, p = 0.008), and improved outcomes with adjuvant chemoimmunotherapy vs. chemotherapy alone (OS: HR 0.10, 95% CI 0.02-0.48, p <0.001; RFS: HR 0.29, 95% CI 0.12-0.70, p = 0.003). The immune-excluded phenotype was stroma-enriched (α-SMA, p <0.001), with immune cells largely restricted to the tumour margin or peritumour regions; the immune-desert phenotype showed sparse immune infiltration. PNI was associated with immunosuppressive chronic inflammation, characterised by enrichment of PD-L1+ myeloid cells and exhausted CD8+ T cells near invaded nerve bundles (cell density, p <0.001). Transcriptomic analyses suggested enhanced tumour neurotropism in PNI-positive tumours (gene-set enrichment, p <0.05), together with activation of IL-6/IGF-1 related chronic inflammatory signalling and lipid-metabolic rewiring involving LEP, CD36, and ADIPOQ, collectively shaping a local immune-evasion niche (FDR <0.05).
CONCLUSIONS: We defined three spatial immunophenotypes in GBC with distinct immune features and clinical outcomes. PNI was associated with the formation of a local immune-evasion niche.
IMPACT AND IMPLICATIONS: GBC lacks validated biomarkers to guide postoperative immunotherapy, whereas spatial immune architecture provides a clinically meaningful indicator of tumour immune heterogeneity. By defining three spatial immunophenotypes, we delineate their distinct clinical outcomes and immune-evasion features. Moreover, we demonstrate an association between PNI and the formation of a local immune-evasion niche. These findings may inform clinicians and clinical trialists seeking to optimise postoperative risk stratification and adjuvant treatment strategies, and researchers investigating PNI-related molecular mechanisms. Clinically, integrating spatial immunophenotyping with PNI assessment into routine pathology workflows may improve prognostic stratification and inform adjuvant treatment decisions; however, prospective validation is required before broad clinical adoption.

Keywords: Gallbladder cancer; Immune evasion; Multiplex immunohistochemistry; Perineural invasion; Spatial immunophenotype

DOI: https://doi.org/10.1016/j.jhepr.2026.101807

Front Immunol. 2026 ;17 1801614

Breast cancer brain metastasis: from molecular insights to therapeutic innovation.

Xiaoxi Han, Wenjie Ma, Wenhui Zhao.

Breast cancer is the most common malignancy in women and a major cause of cancer-related mortality. While early-stage disease is often curable, many patients ultimately develop distant metastases, with the brain representing one of the most devastating sites. Breast cancer brain metastasis (BCBM) is particularly prevalent in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes, leading to severe neurological symptoms, diminished quality of life, and poor prognosis. Despite progress in systemic therapy for primary tumors, outcomes for patients with BCBM remain poor, and these patients are frequently excluded from clinical trials. The pathogenesis of BCBM involves complex interactions between tumor cells and the central nervous system microenvironment. Crossing the blood-brain barrier and adapting to the brain niche requires tumor-stroma crosstalk, including signaling with astrocytes and microglia, which promotes immune evasion, therapeutic resistance, and metastatic outgrowth. Although advances in preclinical models and molecular profiling have provided valuable insights, critical mechanisms remain incompletely understood. Systemic therapies are increasingly important, with HER2-targeted agents, tyrosine kinase inhibitors, and subtype-specific regimens showing activity. Novel approaches, including poly (ADP-ribose) polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidylinositol 3-kinase inhibitors, and antibody-drug conjugates, are under evaluation. This review synthesizes epidemiology, molecular mechanisms, and emerging therapies of BCBM, underscoring advances achieved and highlighting the urgent need for novel targeted strategies and inclusive clinical trials.

Keywords: brain metastasis; breast cancer; molecular mechanism; prognosis; therapeutic targets

DOI: https://doi.org/10.3389/fimmu.2026.1801614

Cancers (Basel). 2026 Mar 27. pii: 1095. [Epub ahead of print]18(7):

Evaluating the Translation Value of Two In Vivo Models for Breast Cancer Brain Metastases.

Sigrid Cold, Maria Zeiler Alfsen, Brandur Halgirsson, Mads Neergaard Jorgensen, Jacob Hald, Carsten Haagen Nielsen, Andreas Kjaer, Lotte Kellemann Kristensen, Trine Bjornbo Engel.

BACKGROUND: Breast cancer brain metastases (BCBM) lack effective treatments, contributing to breast cancer-related morbidity and mortality. Integrating translational animal models and advanced non-invasive imaging can accelerate the development of urgently needed therapies.
METHOD: In this study, we developed an intracarotid method mimicking BCBM and compared it to the stereotactic model in terms of animal welfare, tumour establishment, and blood-brain barrier (BBB) permeability. BCBM was established through intracarotid or stereotactic inoculation of BT474 and MDA-MB-231.Luc2 cells in NMRI nude mice. We utilised magnetic resonance imaging (MRI) and bioluminescence imaging (BLI) to monitor tumour growth and BBB permeability, supported by fluorescent immunohistochemistry for validation. Finally, light sheet microscopy (LSM) was employed to visualise tumour establishment in intact brains.
RESULTS: Both inoculation methods achieved a survival rate > 70%, with animals recovering within a week post-surgery. MRI and BLI effectively visualised tumour growth with stereotactic implantation, resulting in single tumours, while intracarotid inoculation led to micro-seeding of up to seven tumours in one brain. Tumour growth was rapid and homogenous in the stereotactic model, whereas the intracarotid model exhibited slower, heterogenous growth. Notably, BBB permeability was significantly higher in small tumours in the stereotactic model when compared to the intracarotid model (p = 0.003). Ex vivo analyses validated these findings with the identification of multiple metastasis in the intracarotid model and single tumours in the stereotactic model.
CONCLUSIONS: We developed an animal model that closely mimics BCBM, highlighting extravasation and micro-seeding while maintaining animal welfare. Our established imaging protocols enable longitudinal evaluations of BBB permeability and treatment response, creating a translational platform for testing novel anti-cancer therapies.

Keywords: brain metastasis; breast cancer; imaging; intracarotid inoculation; orthotopic model

DOI: https://doi.org/10.3390/cancers18071095