bims-netuvo Biomed News
on Nerves in tumours of visceral organs
Issue of 2026–04–05
sixteen papers selected by
Maksym V. Kopanitsa, Charles River Laboratories
  1. Cancer Neuroscience: Dissecting Autonomic and Sensory Neural Regulation of Tumor Progression and Therapeutic Resistance.
  2. Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming.
  3. Interactions Between the Nervous System and PDAC Progression: Regulatory Mechanisms and Therapeutic Implications.
  4. CT-based intratumoral, peritumoral radiomics and clinical features: a combined model for perineural invasion prediction in PDAC.
  5. Neuro-immune crosstalk in breast cancer: molecular mechanisms from stress signals to immune escape.
  6. Targeting the sensory-sympathetic axis for cancer immunotherapy.
  7. Tumor-derived JAG2 programs macrophages via NOTCH3 to drive perineural invasion in colorectal cancer.
  8. Peripheral Nerve-Cancer Interactions in the Tumor Microenvironment: A Three-Dimensional Framework Integrating Mechanisms, Modulators, and Therapeutic Strategies.
  9. Cancer pain: current practice and emerging targets.
  10. Predictive score for perineural invasion in colorectal cancer: A SEER-based case-control analysis.
  11. The neuro-vascular-immune triad: the interactive network in the tumor microenvironment.
  12. Preventive strategies against brain metastases: current state of the art and future directions.
  13. Single-cell landscape of intratumoral heterogeneity and GABA-mediated remodeling of the immune microenvironment in breast cancer metastases.
  14. Preventive Role and Survival Benefit of Beta Blockers in Pancreatic Cancer: A Systematic Review and Meta-Analysis of Observational Studies.
  15. Targeting the neuro-immune crosstalk in breast cancer brain metastases.
  16. Neural proximity, vascular remodeling, and perineural immune exclusion across the cervical neoplasia spectrum - a whole-slide, nerve-anchored spatial analysis of 135 cases.
  1. Cancer Lett. 2026 Mar 27. pii: S0304-3835(26)00223-5. [Epub ahead of print] 218460
    Cancer Neuroscience: Dissecting Autonomic and Sensory Neural Regulation of Tumor Progression and Therapeutic Resistance.
    Jiaxin Sun, Chen Zhang, Jinmiao Zhong, Bing Zhou.
      The pathological features of invasion and metastasis in malignant tumors are intricately intertwined with the tumor microenvironment (TME). Recent investigations underscore that, alongside immune cells, blood vessels, and the lymphatic system, the nervous system emerges as a pivotal player within the TME. Tumors possess the remarkable ability to modify and even co-opt the architecture and functions of the nervous system, creating a dynamic interplay. Furthermore, aberrant neuronal activation has the potential to accelerate tumor progression. This review summarizes the emerging field of cancer neuroscience, encompassing both direct neuro-cancer cell communication and indirect interactions mediated through other TME components. It further outlines the commonly used experimental tools, cutting-edge technologies, and potential therapeutic targets identified along neuro-cancer interaction pathways. By elucidating the reciprocal interplay between the nervous system and tumors, this area of research offers new perspectives for understanding tumorigenesis and provides promising molecular targets and strategies for cancer therapy.
    DOI:  https://doi.org/10.1016/j.canlet.2026.218460
  2. Cell Rep. 2026 Mar 28. pii: S2211-1247(26)00286-X. [Epub ahead of print]45(4): 117208
    Regulation of neuronal invasion of small cell lung cancer by STMN2/β-alanine-controlled metabolic reprogramming.
    Yan Zhou, Runbo Zhong, Yanwei Zhang, Michael R Shurin, Galina V Shurin, Liwen Xiong, Tianqing Chu, Baohui Han, Haohua Teng, Yu Yang, Erpeng Wu, Chi Zhang, Lincheng Zhang, Wanting Liu, Yuqing Lou, Jun Lu, Yongjie Wang, Hua Zhong.
      Small cell lung cancer (SCLC) exhibits a high incidence of perineural invasion (PNI), a clinical feature associated with poor prognosis. Here, we establish PNI as an independent adverse prognostic factor in a surgical SCLC cohort. We further show that the neural microenvironment upregulates stathmin-2 (STMN2) in SCLC cells. STMN2, in a concentration-dependent manner, activates the β-alanine metabolic pathway, leading to intracellular β-alanine accumulation, which enhances tumor cell migration and invasion. In vivo, STMN2 knockdown suppresses neural invasion, an effect reversible upon β-alanine supplementation. This work defines a neural-STMN2-β-alanine-invasion axis that drives PNI in SCLC, providing mechanistic insights and highlighting a promising metabolic vulnerability for therapeutic intervention.
    Keywords:  CP: cancer; CP: neuroscience; SCLC; invasiveness; perineural invasion; stathmin-2
    DOI:  https://doi.org/10.1016/j.celrep.2026.117208
  3. Eur J Pharmacol. 2026 Mar 30. pii: S0014-2999(26)00311-0. [Epub ahead of print] 178829
    Interactions Between the Nervous System and PDAC Progression: Regulatory Mechanisms and Therapeutic Implications.
    Joelson Germano Crispim, Camila Neiva Porto Silva, Moacyr Jesus Barreto de Melo Rêgo, Michelle Melgarejo da Rosa.
      Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human cancers. This review highlights recent advances in understanding how central and peripheral neural activity shapes PDAC, with a focus on signaling pathways, cellular mediators, and emerging research directions. Sympathetic fibers foster a pro-tumorigenic microenvironment through catecholamine release, while parasympathetic inputs can exert context-dependent inhibitory effects. Sensory pathways, Schwann cells, and neurotrophic factors further remodel the tumor niche, enabling invasion and immune escape. At the systemic level, stress responses amplify this neuro-tumor crosstalk, accelerating disease progression. Therapeutically, strategies that disrupt neural cues-such as β-blockers, Trk inhibitors, or selective denervation-are showing promise in preclinical and early clinical studies. By revealing how PDAC exploits neural mechanisms, this work underscores the potential of neuro-targeted therapies to complement conventional approaches and reshape the future of pancreatic cancer treatment.
    Keywords:  Neuro-tumor crosstalk; Neuroplasticity in cancer; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ejphar.2026.178829
  4. J Cancer Res Clin Oncol. 2026 Mar 28. pii: 77. [Epub ahead of print]152(3):
    CT-based intratumoral, peritumoral radiomics and clinical features: a combined model for perineural invasion prediction in PDAC.
    Qi Lan, Yuying Wang, Fan Xia, Yalin Sun, Yingying Cao, Zhongqiu Wang.
       PURPOSE: To develop and validate a general radiomics nomogram capable of identifying perineural invasion (PNI) status in pancreatic ductal adenocarcinoma (PDAC) patients.
    METHODS: A total of 175 pancreatic cancer patients were retrospectively enrolled in this study. Patients were randomly divided into a training cohort (n = 123) and a test cohort (n = 52) at a ratio of 7:3. Senior physicians manually delineated the intratumoral region of interest (ROI), and the peritumoral ROI was obtained by expanding 3 mm outward from the intratumoral ROI. After extracting and selecting radiomics features, the ExtraTrees algorithm was used to construct intratumoral, peritumoral, and intratumoral + peritumoral radiomics models, respectively. The optimal radiomics model was selected to construct a combined model with clinical characteristics. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the predictive performance of the models.
    RESULTS: Multivariate analysis showed that carbohydrate antigen 199 (CA199) (p < 0.05) and vascular invasion (p < 0.05) were associated with an increased risk of PNI. In the training cohort, the area under the curve (AUC), sensitivity, and specificity of the combined model were 0.855, 76.8%, and 80.5%, respectively; in the test cohort, they were 0.844, 76.5%, and 77.8%, respectively. The performance of the combined model was superior to that of the clinical model or radiomics model alone.
    CONCLUSIONS: The combined predictive model integrating intratumoral + peritumoral radiomics features based on contrast-enhanced computed tomography (CE-CT) with clinical characteristics can effectively predict PNI in pancreatic cancer.
    Keywords:  Computed tomography; Pancreatic ductal adenocarcinoma; Perineural invasion; Radiomics
    DOI:  https://doi.org/10.1007/s00432-026-06462-4
  5. Front Immunol. 2026 ;17 1790195
    Neuro-immune crosstalk in breast cancer: molecular mechanisms from stress signals to immune escape.
    Gaofeng Ni, Nuan Qian, Ying Jiang, Rui Tian, Tianjiao Huang, Shuyan Li.
       Background: Breast cancer (BC) exhibits marked biological heterogeneity and remains a major cause of cancer-related death in women. With advances in molecular subtyping and tumor microenvironment research, the nervous system has emerged as an important regulator of BC initiation, progression, and metastasis. Tumor-associated nerves influence cancer not only locally through sympathetic, parasympathetic, and sensory innervation, but also systemically by modulating immunity via psychological stress, circadian rhythms, and neuroendocrine pathways.
    Results: Increasing evidence shows that nerve fiber density is elevated in BC tissues and correlates with greater invasiveness and poorer prognosis. The sympathetic nervous system promotes tumor growth, angiogenesis, and metastasis mainly through β-adrenergic signaling and suppression of anti-tumor immunity. Chronic psychological stress further enhances tumor-promoting immune changes through sustained neuroendocrine activation. In contrast, parasympathetic signaling may exert inhibitory effects on tumor progression, while sensory nerves and neuropeptides display context-dependent roles in inflammation, pain, and immune regulation. Moreover, circadian rhythm disruption and reduced melatonin impair tumor immune surveillance. Clinical and retrospective studies suggest that neural-targeted interventions, such as β-blockers and psychological therapies, may improve the immune microenvironment and clinical outcomes in BC.
    Conclusion: The nervous system plays a crucial role in shaping the BC microenvironment and promoting immune escape through complex, multi-level mechanisms. Different types of nerves exert distinct effects on tumor progression. Targeting neuro-immune interactions may therefore offer a promising strategy for adjuvant BC therapy.
    Keywords:  breast cancer; circadian rhythms; innervation; neuro-immune interaction; parasympathetic nerve; sympathetic nerve
    DOI:  https://doi.org/10.3389/fimmu.2026.1790195
  6. Trends Pharmacol Sci. 2026 Mar 31. pii: S0165-6147(26)00063-5. [Epub ahead of print]
    Targeting the sensory-sympathetic axis for cancer immunotherapy.
    Wei-Lin Jin, Ming-Zhu Jin.
      How tumors manipulate neural circuits to evade immunity is unclear. In a recent study, Wei et al. reveal, in lung adenocarcinoma, a vagal sensory-brain stem sympathetic circuit that suppresses macrophages and CD8+ T cells via β2-adrenergic signaling. Disrupting this axis restores antitumor immunity, nominating β-blockers and neural modulation as promising therapies.
    Keywords:  ADRB2; cancer neuroscience; drug repurposing; immunosuppression; sensory–sympathetic axis; tumor–brain crosstalk
    DOI:  https://doi.org/10.1016/j.tips.2026.03.003
  7. Int J Biol Macromol. 2026 Mar 29. pii: S0141-8130(26)01650-8. [Epub ahead of print] 151724
    Tumor-derived JAG2 programs macrophages via NOTCH3 to drive perineural invasion in colorectal cancer.
    Enen Zhao, Ruihan Liu, Na Chen, Chi Zhou, Dagui Lin, Xinmiao Liang, Jiangbangrui Chu, Liren Li, Linjie Zhang.
      Perineural invasion (PNI) is an important route of dissemination in colorectal cancer (CRC) and is associated with recurrence and poor prognosis, but the underlying immune-tumor mechanisms remain insufficiently defined. We integrated patient-derived data with in vitro and in vivo models to investigate the role of tumor-macrophage signaling in CRC-associated PNI. Single-cell transcriptomic and ligand-receptor analyses identified tumor-derived JAG2 and macrophage NOTCH3 as a PNI-associated communication axis, with enrichment of JAG2-positive tumor epithelial cells and NOTCH3-positive macrophages in nerve-adjacent regions. Functional studies showed that activation of this axis induced STAT3 phosphorylation and increased CCL2 expression in macrophages, supporting STAT3-mediated transcriptional upregulation of CCL2. These macrophages exhibited an immunosuppressive M2-like phenotype with increased neurotrophic and chemotactic mediators and promoted tumor migration and neurotropic behavior in vitro. Disruption of JAG2-NOTCH3 signaling, STAT3 inhibition, or blockade of the CCL2 arm attenuated these effects. Across in vivo models, pathway inhibition reduced tumor growth, decreased CD206-positive tumor-associated macrophages, and attenuated sciatic nerve invasion. Together, these findings identify a targetable JAG2-NOTCH3-STAT3-CCL2 signaling programmed through which CRC cells reprogramed macrophages to establish a neurotropic microenvironment permissive for PNI, suggesting potential therapeutic strategies to limit neural dissemination in CRC.
    Keywords:  Colorectal cancer; JAG2; NOTCH3; Perineural invasion; Tumor microenvironment; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151724
  8. Research (Wash D C). 2026 ;9 1221
    Peripheral Nerve-Cancer Interactions in the Tumor Microenvironment: A Three-Dimensional Framework Integrating Mechanisms, Modulators, and Therapeutic Strategies.
    Fanglin Shao, Jie Wang, Aiqing Li, Ruicheng Wu, Jiamin Chen, Zhouting Tuo, Dilinaer Wusiman, Koo Han Yoo, Wuran Wei, Zhipeng Wang, Dengxiong Li, Qi Zhang, Yuanning Guo, Dechao Feng.
      The nervous system has emerged as a critical regulator of tumor biology. Over the past 2 decades, accumulating evidence has given rise to the rapidly expanding field of cancer neuroscience, revealing that neural circuits actively shape tumor initiation, progression, metastasis, prognosis, and therapeutic response. While the nervous system comprises both central and peripheral components, increasing attention has focused on the peripheral nervous system (PNS) as a key mediator of tumor-host interactions within the tumor microenvironment (TME). Autonomic (sympathetic, parasympathetic, and enteric) and sensory neural pathways interact dynamically with tumor cells, immune cells, glial cells, and other stromal components, influencing tumor growth, invasion, metastasis, and immune regulation through diverse cellular and molecular mechanisms. In addition, environmental and patient pathophysiological factors-including environmental stress, psychological states, pain, microbiota, aging, metabolic status, and lifestyle behaviors-can further modulate nerve-cancer interactions and reshape the tumor ecosystem. In this review, we systematically organize PNS-cancer interactions within the TME across 3 integrative dimensions: pathological phenotypes, cellular components, and modes of communication, thereby providing a conceptual framework for understanding the mechanistic landscape of cancer neuroscience. This structured perspective highlights the diverse modalities of nerve-tumor communication, identifies key modulatory factors influencing these interactions, and discusses emerging therapeutic strategies targeting nerve-cancer signaling.
    DOI:  https://doi.org/10.34133/research.1221
  9. Br J Pharmacol. 2026 Apr 03.
    Cancer pain: current practice and emerging targets.
    Yi Ye, Marcin Chwistek, Zhiting Gong, Vanessa Uzonwanne, Xiaojie Shi, Arpad Szallasi.
      Cancer pain (CP) arises from a complex interplay between the tumour and its microenvironment. Many patients experience a mixed pain phenotype that encompasses nociceptive, neuropathic and neuroinflammatory mechanisms, and vary across tumour type and disease stage. Despite decades of intensive research, the mainstay of cancer pain treatment is still non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Recent advances in cancer neuroscience have provided novel insights into the neurobiology of cancer pain. The emerging picture of cancer pain is a disorder of aberrant crosstalk between the tumour, the sensory innervation that the tumour creates and the immune cells that these nerves attract. Precision approaches to disrupt this aberrant pain signalling cascade are guided by newly recognized molecular mechanisms. Here, we review the current practice of cancer pain management and the emerging future of personalized, mechanism-driven pain therapy in oncology.
    Keywords:  aberrant pain signalling; cancer neuroscience; cancer pain; resiniferatoxin; tumor microenvironment
    DOI:  https://doi.org/10.1111/bph.70410
  10. Surgery. 2026 Apr 01. pii: S0039-6060(26)00093-0. [Epub ahead of print]194 110171
    Predictive score for perineural invasion in colorectal cancer: A SEER-based case-control analysis.
    Sameh Hany Emile, Mona Hany Emile, Zoe Garoufalia, Anjelli Wignakumar, Steven D Wexner.
       BACKGROUND: Although perineural invasion, a negative prognosticator in colorectal cancer, is typically detected after surgical resection, preoperative prediction may be useful. We used a large population-based registry to develop a predictive model of perineural invasion in colorectal cancer, including clinical and pathologic features of tumors.
    METHODS: Retrospective case-control analysis of patients with colorectal adenocarcinoma from the Surveillance, Epidemiology, and End Results Research Data database. The study involved a case-control analysis of predictive factors of perineural invasion in colorectal cancer. The main outcome measures were perineural invasion, overall survival, and cancer-specific survival.
    RESULTS: The study included 223,468 patients (52% male, mean age: 66.4 years). Perineural invasion was detected in 13.1%. Independent predictors of perineural invasion were age (odds ratio [OR], 0.99; P < .001), male sex (OR, 1.05; P = .009), Black race (OR, 1.19; P < .001), American Indian race (OR, 0.69; P = .001), left colon cancer (OR, 1.29; P < .001), rectal cancer (OR, 1.32; P < .001), moderately differentiated adenocarcinomas (OR, 1.41; P < .001), poorly differentiated adenocarcinomas (OR, 2.28; P < .001), undifferentiated carcinomas (OR, 2.13; P < .001), mucinous adenocarcinomas (OR, 0.64; P < .001), N1 stage (OR, 2.28; P < .001), N2 stage (OR, 3.83; P < .001), and elevated carcinoembryonic antigen levels (OR, 1.45;P < .001). These predictors were integrated into a risk prediction score, with an excellent negative predictive value of 93%. Perineural invasion was associated with lower 5-year overall survival (54 vs. 76.4%; P < .001) and cancer-specific survival rates (56.6 vs 81.8%; P < .001).
    CONCLUSIONS: Age, sex, race, tumor location, histology and grade, lymph node involvement, and carcinoembryonic antigen levels were independently associated with perineural invasion. Perineural invasion was an independent predictor of liver and lung metastases and worse overall survival and cancer-specific survival. The Cleveland Clinic Florida-Perineural Invasion Prediction score had an excellent negative predictive value in excluding patients without perineural invasion. Pending those trials, these findings may be considered in multidisciplinary team management conferences and in shared decision-making.
    DOI:  https://doi.org/10.1016/j.surg.2026.110171
  11. Cell Commun Signal. 2026 Mar 30.
    The neuro-vascular-immune triad: the interactive network in the tumor microenvironment.
    Dan Li, Qingqing Zhao, Li Liu, Feng Zeng.
      
    Keywords:  Cancer neuroscience; Combination therapy; Neuro-vascular-immune triad; Tumor innervation; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12964-026-02847-7
  12. Neurol Res Pract. 2026 Apr 02. pii: 21. [Epub ahead of print]8(1):
    Preventive strategies against brain metastases: current state of the art and future directions.
    Franziska Maria Ippen, Franz Felix Konen, Peter Hau, Frank Winkler.
      
    Keywords:  Brain metastases; Cancer neuroscience; Prevention; Preventive strategies
    DOI:  https://doi.org/10.1186/s42466-026-00467-7
  13. Breast Cancer Res. 2026 Mar 31.
    Single-cell landscape of intratumoral heterogeneity and GABA-mediated remodeling of the immune microenvironment in breast cancer metastases.
    Lina Tang.
      
    Keywords:  Breast cancer; GABA; Immune microenvironment; Metastasis; Single-cell analysis; Tumor innervation
    DOI:  https://doi.org/10.1186/s13058-026-02268-x
  14. Cureus. 2026 Feb;18(2): e104240
    Preventive Role and Survival Benefit of Beta Blockers in Pancreatic Cancer: A Systematic Review and Meta-Analysis of Observational Studies.
    Suprabhat Giri, Sidharth Harindranath, Prajna Anirvan, Manan Trivedi, Saroj K Sahu, Dibya L Praharaj, Bipadabhanjan Mallick, Preetam Nath, Sridhar Sundaram, Sarat Chandra Panigrahi, Manoj K Sahu.
      Beta-adrenergic receptor stimulation has been reported to positively influence the development and growth of many cancers in animal models. Studies have shown conflicting results regarding the benefit of beta-adrenergic receptor blockers in pancreatic cancer. Hence, we conducted a meta-analysis to investigate the relationship between beta-blocker usage and the prevention of pancreatic cancer and the prognosis after the diagnosis of pancreatic cancer. We searched electronic databases of Medline, Embase, and Scopus from January 2000 to August 2025 to identify studies reporting the relationship between beta-blockers and the development of new pancreatic cancer or survival in diagnosed cases of pancreatic cancer. Adjusted hazard ratios (aHR) were extracted for survival and pooled using a random-effects meta-analysis. One case-control and 13 cohort studies were identified, of which four analyzed the association between beta-blocker use and the incidence of pancreatic cancer, while the other 10 analyzed survival outcomes with the use of beta-blockers in patients with diagnosed pancreatic cancer. The pooled data showed that beta-blockers were significantly associated with a reduced incidence of pancreatic cancer (aHR = 0.77, 95% CI = 0.61 - 0.97, 3 studies). Similarly, continued use of beta-blockers after the diagnosis of pancreatic cancer was associated with improved survival (aHR 0.91, 95% CI: 0.87 - 0.94, 4 studies). However, the use of beta-blockers prior to diagnosis of pancreatic cancer did not improve survival (aHR 0.99, 95% CI: 0.94 - 1.05, 5 studies). The results of the current meta-analysis revealed that beta-blockers have a preventive and protective role against pancreatic cancer. Further research is required to validate the findings of this meta-analysis.
    Keywords:  advanced pancreatic cancer; beta-adrenergic blocker; pancreatic-biliary cancer; survival analysis; systematic review and meta analysis
    DOI:  https://doi.org/10.7759/cureus.104240
  15. J Immunother Cancer. 2026 Apr 02. pii: e014134. [Epub ahead of print]14(4):
    Targeting the neuro-immune crosstalk in breast cancer brain metastases.
    Yutian Zou, Jiadi Wu, Ze Yuan, Xiaofang He, Hailin Tang.
      Breast cancer brain metastasis (BCBrM) remains one of the most lethal manifestations of breast cancer. Its response to immunotherapy is severely limited by the blood-brain barrier, which restricts immune cell infiltration and antigen presentation, thereby creating an immunosuppressive microenvironment. To overcome these barriers, recent studies have focused on novel immune checkpoints, including the Lymphocyte-Activated Gene 3-Galectin 3 (LAG3-LGALS3) and T-Cell Immunoreceptor with Ig and ITIM Domains-Nectin Cell Adhesion Molecule 2 (TIGIT-NECTIN2) axes, as well as on the reprogrammed metastatic ecosystem driven by immunosuppressive cells such as Forkhead Box P3-positive (FOXP3⁺) Regulatory T (Treg) cells, Lysosomal-Associated Membrane Protein 3-positive (LAMP3⁺) tolerogenic dendritic cells (DCs), C-C Motif Chemokine Ligand 18-positive (CCL18⁺) M2-like macrophages, Regulator of G-Protein Signaling 5-positive (RGS5⁺) cancer-associated fibroblasts (CAFs), Galectin 1-positive (LGALS1⁺) and TANK-Binding Kinase 1-positive (TBK1⁺) microglia, and phosphorylated Signal Transducer and Activator of Transcription 3-positive (pSTAT3⁺) reactive astrocytes. In addition, targeted inhibition of tumor-derived N-acetyltransferase 8-like (NAT8L) and metabolites N-Acetylaspartate (NAA), suppression of the N-Methyl-D-Aspartate Receptor (NMDAR) signaling pathway in tumor cells, and interventions against γ-Aminobutyric Acid (GABA)ergic reprogramming in BCBrM cells. Moreover, targeted interventions against distinct immune escape pathways-such as the Ubiquitin-Conjugating Enzyme E2T (UBE2T)/Cell Division Cycle 42 (CDC42)/Cluster of Differentiation 276 (CD276) and C-C Motif Chemokine Ligand 2-C-C Motif Chemokine Receptor 2/C-C Motif Chemokine Receptor 4 (CCL2-CCR2/CCR4) axes-have shown promise in reshaping the immune microenvironment and enhancing the efficacy of conventional immunotherapy. Collectively, this perspective outlines evolving strategies in immune checkpoint modulation, cellular ecosystem reprogramming, and neuroimmune intervention, providing a forward-looking framework to enhance the efficacy of immunotherapy in BCBrM.
    Keywords:  Breast Cancer; Immune Checkpoint Inhibitor; Immunosuppression; Immunotherapy; Tumor microenvironment - TME
    DOI:  https://doi.org/10.1136/jitc-2025-014134
  16. Pol J Pathol. 2025 ;pii: 57485. [Epub ahead of print]76(4): 318-328
    Neural proximity, vascular remodeling, and perineural immune exclusion across the cervical neoplasia spectrum - a whole-slide, nerve-anchored spatial analysis of 135 cases.
    Giorgi-Jemal Gogitidze, Shota Kepuladze, George Burkadze.
      Cervical carcinogenesis unfolds within a complex tissue ecosystem. While epithelial biomarkers and HPV status inform risk, the contribution of local neural circuits and their relationship to angiogenesis and cytotoxic immunity remains insufficiently defined in cervical intraepithelial neoplasia (CIN). In a balanced, archival cohort (n = 135; 27 per group: normal, CIN1, CIN2, CIN3, squamous cell carcinoma - SCC), whole-slide images were analyzed using a pre-specified QuPath pipeline with fixed thresholds and area normalization. We created composite indices: a neuro-epithelial coupling index (NECI) integrating nerve density, caliber, PGP9.5 signal, and inverse nerve-basement membrane (BM) distance; a vascular remodeling index (VRI) integrating CD31/CD34 microvessel density, vascular endothelial growth factor, vessel caliber, and peribasement vessels. Cytotoxic access was captured by CD8 density within 0-50 µm of nerves (NACD50) NECI and VRI increased monotonically with grade (group medians, normal  SCC: NECI -1.29, -0.64, 0.00, 1.33, 3.54; VRI -1.35, -0.58, 0.00, 1.14, 2.06). Neurovascular progression index values differ between grades (-1.32, -0.64, 0.00, 1.24, 2.66). The minimum nerve-BM distance shortened stepwise. In contrast, nerve-adjacent CD8 access declined with grade: NACD50 fell (≈ 5, 8, 4, 2, 1 cells/mm²) and nerve-avoidance ratio decreased (≈ 0.9, 0.8, 0.6, 0.4, 0.3), indicating progressive perineural CD8 exclusion. Across the full histologic spectrum, neuro-epithelial proximity and vascular remodeling intensify, whereas cytotoxic access to the perineural niche declines. These nerve-anchored, spatially explicit metrics add a neural dimension to cervical carcinogenesis and nominate the 0-50 µm perineural zone as a quantifiable compartment for risk stratification and interventional trials. External validation and calibrated modeling are warranted.
    Keywords:   CD8 T-cells; angiogenesis; perineural niche; tumor microenvironment; whole-slide imaging; cervical intraepithelial neoplasia
    DOI:  https://doi.org/10.5114/pjp.2025.158907
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