The Journal of Pathology最新文献

{"title":"Periostin-IHH feedforward loop promotes hepatocellular carcinoma development by enhancing hepatic fibrosis and tumor cell proliferation.","authors":"Bin Liu, Xuebin Li, Menghao Zhang, Xingxing Liu, Junxing Sun, Mingjiao Deng, Gaoliang Ouyang, Tiantian Wu","doi":"10.1002/path.6467","DOIUrl":"https://doi.org/10.1002/path.6467","url":null,"abstract":"<p><p>The extracellular matrix protein periostin plays a critical role in the progression of hepatic fibrosis and hepatocellular carcinoma (HCC). However, little is known about how periostin regulates both hepatic fibrosis and tumor growth in the progression of HCC. Here we demonstrate that periostin deficiency impairs HCC development and decreases tissue stiffness of liver tumors in DEN/CCl₄-treated mice. Increased matrix stiffness enhanced periostin expression in hepatic stellate cells (HSCs). The combination of periostin and increased stiffness synergistically promoted HCC cell proliferation in vitro. Moreover, periostin deficiency in HSCs impaired both HSC-promoted and stiffness-increased HCC cell proliferation in vivo. We further demonstrated that periostin promotes Indian hedgehog (IHH) expression in HCC cells through the integrin-PYK2-TAZ pathway. Conversely, IHH increased the expression of periostin in HSCs via GLI2. Periostin expression positively correlates with fibrotic features and IHH signaling in clinical HCC tissues. Collectively, these findings indicate that periostin and IHH cooperatively contribute to the development of HCC by regulating the tumor-stroma crosstalk via the periostin-integrin-PYK2-TAZ-IHH pathway in tumor cells and IHH-GLI2-periostin signaling in HSCs. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145038800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Investigating the mechanisms of indocyanine green tumour uptake in sarcoma cell lines and ex vivo human tissue.","authors":"Corey David Chan, Marcus J Brookes, Toni A Pringle, Rahul Pal, Riya Tanwani, Alastair D Burt, James C Knight, Anand Tn Kumar, Kenneth S Rankin","doi":"10.1002/path.6473","DOIUrl":"https://doi.org/10.1002/path.6473","url":null,"abstract":"<p><p>Indocyanine green (ICG) is a well-established near-infrared dye which has been used clinically for several decades. Recently, it has been utilised for fluorescence-guided surgery in a range of solid cancer types, including sarcoma, with the aim of reducing the positive margin rate. The increased uptake and retention of ICG within tumours, compared with normal tissue, gives surgeons a visual reference to aid resection when viewed through a near-infrared camera. However, the mechanisms of this process are poorly understood. We performed in vitro ICG cellular uptake studies across a panel of sarcoma cell lines exhibiting varying proliferation rates and phenotypes. The effects of ICG concentration, incubation time, inhibition of clathrin-mediated endocytosis, and cell line proliferation rate on the cellular uptake of ICG were investigated using fluorescence microscopy and flow cytometry. Subcellular localisation of intracellular ICG was assessed via colocalization with a lysosomal marker. The spatial distribution of ICG in patient tumour tissue following fluorescence-guided surgery was assessed by high-resolution tissue imaging and quantified using fluorescence lifetime imaging. In vitro results showed that the cell line proliferation rate correlated significantly with ICG uptake (Spearman's rank correlation coefficient = 1.00, p < 0.001), and maximum ICG uptake was observed after 24 h incubation. ICG cellular uptake was significantly reduced by inhibition of clathrin-mediated endocytosis (p = 0.0004), and intracellular ICG significantly colocalized with a lysosomal marker within 30 min (Pearson's r = 0.8). On histological analysis of tumour tissue from three different sarcoma subtypes, ICG was observed within sarcoma cells as well as accumulating in paucicellular areas of haemorrhage and necrosis within the tumour microenvironment. Through quantification of fluorescence lifetime imaging of ICG, we were able to differentiate sarcoma cells from haemorrhage and necrosis within tumour tissue. Combining in vitro data with analysis of patient tissue, we propose that the uptake and accumulation of ICG in sarcomas is driven by a synergistic mechanism involving the enhanced permeability and retention effect combined with active tumour cell endocytosis of the dye. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028695","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell state dynamics during early stages of serous endometrial carcinoma.","authors":"Andrea Flesken-Nikitin, Matalin G Pirtz, Christopher S Ashe, Lora H Ellenson, Anna Yemelyanova, Benjamin D Cosgrove, Alexander Yu Nikitin","doi":"10.1002/path.6470","DOIUrl":"https://doi.org/10.1002/path.6470","url":null,"abstract":"<p><p>Serous endometrial carcinoma (SEC) is one of the most lethal types of uterine cancer, responsible for about 40% of all endometrial cancer-related deaths. Cell state dynamics during the early stages of SEC remain largely unknown, thereby hindering early detection and treatment of this disease. Here, we provide a comprehensive census of cell types and their states for normal, predysplastic, and dysplastic endometrium in a genetic mouse model of SEC. We report that predysplastic changes are characterized by increasingly diverse immature luminal epithelial cell populations. The decrease in differentiated cell states is accompanied by the emergence of a 'single-cell and spatial transcriptome dysregulation' gene signature. This signature contains seven genes that predict poor patient prognosis and are promising diagnostic markers and therapeutic targets. In summary, our results suggest an important role of the luminal epithelial cell state in SEC pathogenesis and validate our mouse SEC model as a capable comparative platform for preclinical studies. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sparking malignancy: nicotine as a driver of stemness and metastasis in triple-negative breast cancer^†.","authors":"Christopher Simpkins, Eneda Toska","doi":"10.1002/path.6475","DOIUrl":"https://doi.org/10.1002/path.6475","url":null,"abstract":"<p><p>Triple-negative breast cancer (TNBC) lacks expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, and remains one of the most aggressive and therapeutically challenging breast cancer subtypes, marked by early relapse, metastasis, and limited targeted treatment options. In a recent study published in The Journal of Pathology, Kuo et al provide compelling evidence that nicotine exposure, whether from tobacco smoke or e-cigarette vapor, drives TNBC progression by promoting stem-like and metastatic phenotypes. Integrating clinical datasets, patient tissues, cell lines, and in vivo models, the authors demonstrate that nicotine enhances tumor aggressiveness via coordinated upregulation of CHRNA9 and IGF1R. Silencing either receptor attenuates nicotine-induced stemness, invasion, and metastasis, revealing a therapeutically actionable axis. High expression of CHRNA9 and IGF1R correlates with poor clinical outcomes and may define a nicotine-exposed TNBC subgroup that could benefit from IGF1R-targeted therapy or repurposed nicotinic receptor antagonists. These findings underscore the role of environmental exposures in shaping tumor biology and offer a mechanistic basis for the poorer prognosis observed in smokers with breast cancer. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of NLRP1 Met1154Val and IL1B variants on gestational malaria: an unexplored role of NLRP1 in inflammasome activation by Plasmodium spp.","authors":"Vinicius Nc Leal, Jessica A Ribeiro, Leticia Girardi Marra, Alexandre Tt Rio, Edione C Reis, Gerhard Wunderlich, Jamille G Dombrowski, Claudio Rf Marinho, Alessandra Pontillo","doi":"10.1002/path.6471","DOIUrl":"https://doi.org/10.1002/path.6471","url":null,"abstract":"<p><p>We hypothesized that variants in inflammasome-related genes could influence susceptibility to gestational malaria (GM). To test this, we conducted an association study in a cohort of pregnant women from a malaria-endemic region in northern Brazil, assessing whether specific functional single nucleotide variants (SNVs) in inflammasome genes affect (1) the response to Plasmodium infection and (2) the development of placental malaria. Our findings revealed that the NLRP1 p.Met1154Val variant was associated with a protective effect against Plasmodium infection. Moreover, IL1B SNVs appeared more prevalent in severe cases. Additionally, multivariate analyses incorporating placental blood cytokines, growth factors, and immunohistochemical features revealed that the NLRP1 p.Met1154Val variant correlated with a healthier placental state, highlighting a potential protective role of the NLRP1 inflammasome in GM. For the first time, we showed that infected red blood cells induce NLRP1- and caspase-1-dependent pyroptosis in BeWo trophoblast cells, identifying a novel inflammasome pathway involved in GM pathogenesis. Our study identifies a genetic variant underlying NLRP1 contribution to GM and suggests that NLRP1 may be an under-explored inflammasome receptor in malaria and infected erythrocytes' sensing. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High-fat diets influence breast cancer progression by modulating CAF-immune cell interactions through PLAT signaling.","authors":"Weihan Li, Jiangshan He, Jingjing Li, Xingyu Xie, Peng Zhou","doi":"10.1002/path.6452","DOIUrl":"10.1002/path.6452","url":null,"abstract":"<p><p>Breast cancer progression is profoundly influenced by interactions within the tumor microenvironment, particularly between cancer-associated fibroblasts and immune cells. This study investigated how cancer-associated fibroblasts impact immune cells in the context of high-fat diets, focusing on key genes involved in these interactions. By analyzing breast cancer-related single-cell and bulk RNA sequencing data, we identified candidate genes in cancer-associated fibroblasts that influence immune cell behavior. Using the TCGA-BRCA dataset, we assessed the correlation between these genes and patient survival, as well as their role in immune cell infiltration and their association with clinical and immunological features. Our findings revealed significant cellular communication under high-fat diet conditions, with the cancer-associated fibroblast marker gene PLAT emerging as a key player linked to immune cell infiltration. Analysis of patient data from the GEO and TCGA-BRCA datasets revealed that in high-fat diet-induced breast cancer, patients exhibited reduced stromal scores, and stromal, immune, and ESTIMATE scores were significantly associated with clinical outcomes. In vivo murine experiments indicated that high-fat diets promoted tumor-associated macrophage infiltration while inhibiting CD4⁺ T-cell activation. In vitro experiments confirmed that reduced PLAT expression facilitated M2 macrophage polarization and promoted cancer cell invasion and migration. Overall, our results highlight that high-fat diets can reshape the tumor microenvironment and accelerate breast cancer progression by modulating cancer-associated fibroblast-immune cell interactions, specifically via PLAT signaling. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"APC-related multiple salivary gland lesions: spatial transcriptomic analysis reveals progressive WNT activation.","authors":"Fiona Chan-Pak-Choon, Catherine Beaumont, José Camacho Valenzuela, Josianne Leblanc, Sonja Dahlum, Reiner Siebert, François Thuot, Marc Pusztaszeri, Jacinthe Chênevert, Paz Polak, Tania Cruz Marino, Barbara Rivera, William D Foulkes","doi":"10.1002/path.6466","DOIUrl":"https://doi.org/10.1002/path.6466","url":null,"abstract":"<p><p>Attenuated familial adenomatous polyposis (AFAP) is a disorder caused by germline pathogenic variants in APC and is characterized by the presence of <100 colonic polyps and a high lifetime risk of developing colorectal cancer. Salivary gland basal cell tumours are uncommon and have not previously been reported in AFAP. We present a family with AFAP and multiple salivary gland tumours, including basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC). The colon and salivary gland tumours showed abnormal nuclear β-catenin staining. Genomic analysis of both parotid BCACs showed copy-number-neutral loss of heterozygosity (CNN-LOH) at the APC locus, implicating loss of full-length APC in the aetiology of parotid BCACs. In contrast, the submandibular BCAC showed a p.(Ile35Thr) CTNNB1 mutation. Spatial transcriptomic analysis revealed a stepwise increase in the expression of WNT pathway genes across the proband's salivary lesions, from benign (intercalated duct hyperplasia and BCAs) to malignant (BCACs). Our results showcase BCA and BCAC as potential new phenotypes of AFAP. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristic miRNA profiles represent clinicopathological diversity of small cell lung cancer.","authors":"Masafumi Horie, Hiroshi Takumida, Hayato Koba, Tsukasa Ueda, Hidenori Tanaka, Masami Suzuki, Yukinobu Ito, Ayumi Ito, Mao Kondo, Hiroshi I Suzuki, Isao Matsumoto, Seiji Yano, Akira Saito, Daichi Maeda","doi":"10.1002/path.6458","DOIUrl":"https://doi.org/10.1002/path.6458","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is classified into distinct molecular subtypes based on the expression patterns of four transcription regulators: achaete-scute homolog 1 (ASCL1), neuronal differentiation 1 (NEUROD1), POU class 2 homeobox 3 (POU2F3), and yes-associated protein 1 (YAP1). MicroRNAs (miRNAs) play critical roles in cancer cellular processes but their subtype-specific implications in SCLC remain underexplored. Out of 46 surgically resected SCLC samples, miRNA visualization through in situ hybridization identified high expression of miR-375 in the ASCL1, NEUROD1, and ASCL1/NEUROD1 subtypes, and miR-9-5p in the POU2F3 subtype. Comprehensive enhancer profiling using SCLC cell lines indicated that miR-375 and miR-9-5p were regulated by super-enhancers in a subtype-specific manner. Multiplex immunohistochemistry by imaging mass cytometry found that the miR-9-5p-high SCLC was characterized by a higher stromal area ratio, increased numbers of CD8⁺ T cells and CD163^- macrophages in the intra-tumoral area, and an increased number of plasma cells in the stromal area, as compared with the miR-9-5p-low SCLC. Finally, clinicopathological analysis revealed that the miR-375-high SCLC was associated with YAP1 downregulation, increased serum pro-gastrin-releasing peptide levels, and poor prognosis. These findings highlight the critical role of super-enhancer-related miRNAs in the diversity of SCLC, and underscore the potential for novel diagnostic and prognostic biomarkers based on these subtype-specific miRNAs. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144937645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"STING inhibition alleviates experimental peritoneal damage: potential therapeutic relevance for peritoneal dialysis.","authors":"Vanessa Marchant, Jorge García-Jiménez, Guadalupe T González-Mateo, Pilar Sandoval, Lucía Tejedor-Santamaria, Sandra Rayego-Mateos, Ricardo Ramos, José A Jiménez-Heffernan, Alberto Ortiz, Anne-Catherine Raby, Manuel López-Cabrera, Adrián M Ramos, Marta Ruiz-Ortega","doi":"10.1002/path.6462","DOIUrl":"https://doi.org/10.1002/path.6462","url":null,"abstract":"<p><p>Peritoneal dialysis (PD) is a widely used kidney replacement therapy for patients with end-stage kidney disease. Nevertheless, long-term exposure to PD fluid can damage the peritoneal membrane, leading to ultrafiltration failure and, ultimately, discontinuation of PD. Investigation of the molecular mechanisms underlying this damage is essential for identifying new therapeutic targets to mitigate peritoneal deterioration in PD patients. To this end, we employed RNA sequencing in a preclinical model of peritoneal injury, induced by prolonged chlorhexidine (CHX) exposure, which revealed cytosolic DNA-sensing signaling as a novel pathway. Next, we demonstrated that key players in this pathway, such as the stimulator of interferon genes (STING) and its downstream signaling effectors (interferon regulatory factor 3, interferon-stimulated genes, and nuclear factor-κB signaling), were upregulated in experimental peritoneal damage. Moreover, increased STING expression was observed in human peritoneal biopsies from patients with PD. Subsequent studies in STING-deficient mice showed reduced proinflammatory gene expression and immune cell infiltration, together with inhibited nuclear factor-κB pathway activation at both early (10 days) and late (30 days) stages of CHX-induced peritoneal injury. STING deficiency also reduced peritoneal membrane thickening, fibrosis, and mesothelial-to-mesenchymal transition (MMT)-related changes in advanced CHX-induced damage. Furthermore, pharmacological inhibition of STING with C-176 attenuated CHX-induced peritoneal inflammation. Macrophages were identified as one of the STING-expressing cell types in the injured peritoneum. Hence, in vitro STING blockade in activated macrophages inhibited MMT in cultured mesothelial cells, suggesting that STING activation in this population may drive peritoneal fibrosis. Additionally, STING deficiency reduced peritoneal inflammation in S. epidermidis-induced peritonitis and decreased adhesion scores in a postsurgical intra-abdominal adhesion model. These findings identify STING as a pivotal mediator of peritoneal injury and support its potential as a novel therapeutic target to prevent PD-associated ultrafiltration failure. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MS4A4A-positive tumor-associated macrophages associate with poor prognosis and T-cell exhaustion in patients with urothelial carcinoma of the bladder.","authors":"Tenghao Yang, Xi Sun, Jiaming Chen, Jinqing Li, Chaoqun Liu, Jingwei Yu, Weiju Meng, Yongqiang Wang, Hao Yu, Jian Huang, Bo Wang","doi":"10.1002/path.6465","DOIUrl":"https://doi.org/10.1002/path.6465","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) have multiple potent functions in cancer representing important therapeutic targets. MS4A4A is a functional TAM marker with controversial implications for prognosis. This study aimed to evaluate the association between MS4A4A⁺ TAM infiltration and clinical outcomes in urothelial carcinoma of the bladder (UCB), as well as their impact on the immune landscape. A total of 400 UCB patients from cohorts at Sun Yat-sen Memorial Hospital were analyzed. Immunohistochemistry was used to quantify MS4A4A⁺ TAMs and assess their spatial distribution alongside various immune components, evaluate the benefit of Bacillus Calmette-Guérin (BCG) immunotherapy, and analyze survival outcomes. Additionally, matched UCB tissues were examined before and after recurrence or progression. We observed that MS4A4A⁺ TAMs were present at higher levels in the stromal region compared to the intratumoral region, and correlated with advanced tumor stage and poor prognosis in both regions. No significant difference was observed in the number of MS4A4A⁺ TAMs before and after recurrence/progression in the same patient. Stromal MS4A4A⁺ TAMs were negatively correlated with BCG efficacy and recurrence-free survival. These TAMs were positively associated with CD8⁺ T cells, Foxp3⁺ regulatory T cells, immune checkpoints (PD-1, LAG-3, HAVcr-2, TIGIT), and anti-inflammatory molecules (TGF-β1, IL-4) in the same respective regions. Additionally, MS4A4A⁺ TAMs expressed high levels of TGF-β1 and HAVcr-2 in UCB tissues. In vitro, IL-4 induced MS4A4A expression in mouse bone marrow-derived macrophages, while Ms4a4a knockdown reduced the anti-inflammatory molecule Arg1 and increased pro-inflammatory molecule Nos2 expression. These findings demonstrate that MS4A4A is a reliable prognostic marker and predictor of BCG response in UCB, highlighting its role in shaping the immune landscape and immunotherapy outcomes. © 2025 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":" ","pages":""},"PeriodicalIF":5.2,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144843955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}