Journal of Cancer最新文献

{"title":"Associations of <i>HMGA2</i> single-nucleotide polymorphisms with clinicopathological features of tongue squamous cell carcinoma in Taiwanese men with distinct lifestyle-related risk factors.","authors":"Yi-Chieh Yang, Chia-Hwa Lee, Yi-Fang Ding, Chiao-Wen Lin, Lun-Ching Chang, Yu-Ching Wen, Shun-Fa Yang, Ming-Hsien Chien","doi":"10.7150/jca.139096","DOIUrl":"10.7150/jca.139096","url":null,"abstract":"<p><strong>Background: </strong>Oral squamous cell carcinoma (OSCC) is a predominant malignancy of the oral cavity, with tongue squamous cell carcinoma (TSCC) accounting for a substantial proportion of cases worldwide. High-mobility group A protein 2 (HMGA2) is a nonhistone chromatin-binding factor implicated in aggressive malignant phenotypes of various human cancers. However, the effects of <i>HMGA2</i> variants on OSCC susceptibility and tumor clinicopathological aggressiveness remain unclear.</p><p><strong>Methods: </strong>We examined the associations of functional <i>HMGA2</i> single-nucleotide polymorphisms (SNPs) with TSCC susceptibility and aggressive tumor characteristics in Taiwanese men. Four tagging SNPs (rs6581658 A>G, rs10573247 T>del, rs968697 T>C, and rs8756 A>C) were genotyped using a TaqMan allelic discrimination assay. In addition, HMGA2 expression patterns, as well as their associations with disease aggressiveness and patient survival outcomes, were analyzed using multiple independent datasets, including TCGA, CPTAC, and GEO.</p><p><strong>Results: </strong>Our results indicated no significant association between the four SNPs and TSCC susceptibility. However, carriers of the rs6581658 G allele had significantly increased risks of large tumors (>T2) and advanced clinical stage (stage III or IV) in the dominant model. Moreover, the rs10573247 variant was significantly associated with an increased risk of lymph node metastasis in patients exposed to environmental carcinogens, including betel quid and cigarette smoke. By contrast, the rs968697 variant exerted a protective effect against advanced disease and lymph node metastasis in patients without such environmental exposure. Analyses of clinical datasets pertaining to an American cohort with head and neck squamous cell carcinoma and a Taiwanese cohort with OSCC revealed that HMGA2 expression was upregulated in tumor tissues and was associated with poor prognosis.</p><p><strong>Conclusion: </strong>These findings suggest potential exposure-stratified association in TSCC and highlight <i>HMGA2</i> polymorphisms as promising biomarkers for risk assessment and disease monitoring in male patients with TSCC.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 10","pages":"1709-1719"},"PeriodicalIF":3.4,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13617415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in CAR-T Cell Therapy: From Structural Design Innovations to Clinical Translation Challenges.","authors":"Haixia Gao, Yuan Fang, Pingjing Zhang, Qijun Qian","doi":"10.7150/jca.134677","DOIUrl":"10.7150/jca.134677","url":null,"abstract":"<p><p>Chimeric Antigen Receptor T cells (CAR-T) therapy represents a groundbreaking technology in the field of tumor immunotherapy. This innovative approach involves the genetic engineering of T cells to specifically identify and eradicate tumor cells, and it has been shown to yield remarkable efficacy in treating hematological malignancies. This article provides a comprehensive overview of the core advancements in CAR-T technology, emphasizing the evolution of the five generations of CAR structures. Furthermore, it explores the latest innovations in transfection techniques, highlighting optimizations and comparative advantages of viral and non-viral vectors. The future of CAR-T therapy is poised to focus on several validated translational directions: the development of universal off-the-shelf CAR-T cell products, the design of multi-target and logic-gated intelligent CAR architectures, innovative in vivo genetic reprogramming platforms, and synergistic combinatorial therapeutic regimens to overcome solid tumour immune suppression. These advancements aim to enhance the specificity, safety, and accessibility of CAR-T therapies. This article seeks to outline the current state of CAR-T technology while providing insights into potential theoretical frameworks and technical pathways for its future evolution.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 9","pages":"1684-1697"},"PeriodicalIF":3.4,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulatory roles of E3 ubiquitin ligase RNF128 in inflammatory diseases and tumors.","authors":"Qiuxiang Xiao, Qidong Liu, Jing Wei, Dalang Yu","doi":"10.7150/jca.138010","DOIUrl":"10.7150/jca.138010","url":null,"abstract":"<p><p>Ring finger protein 128 (RNF128) belongs to the family of transmembrane E3 ubiquitin (Ub) ligases. It mediates substrate-specific ubiquitination as a critical post-translational modification and regulates diverse physiological activities and pathological processes. More importantly, the E3 Ub ligase RNF128 is involved in both innate and adaptive immune responses through ‌Ub-dependent regulation‌ of its target proteins. Dysregulation of RNF128 is associated with the occurrence and development of multiple diseases. In recent years, numerous studies have demonstrated the involvement of RNF128 in the progression of inflammatory disorders and tumors. Nevertheless, mechanistic discrepancies persist regarding its dual pro-/anti-inflammatory and pro-/anti-tumor functions. Furthermore, there remains a lack of systematic evaluation concerning the ‌context-dependent regulatory roles of RNF128 in inflammatory responses and tumorigenesis, as well as its targeted therapeutic landscape. Accordingly, this article comprehensively reviews the structure-function relationships of RNF128, its mechanistic regulation of inflammation and tumor progression, and the existing functional controversies in colorectal cancer. It summarizes potential targeted intervention strategies and clinical translational prospects, highlights current research limitations, and proposes future investigative directions. This review aims to provide scientific references for further mechanistic exploration of RNF128 and the development of precision therapeutic strategies for related diseases.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 9","pages":"1671-1683"},"PeriodicalIF":3.4,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573296/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming Resistance to PARP Inhibitors in BRCA-Mutated Cancers: Mechanisms and Therapeutic Strategies.","authors":"Jiahui Guo, Yilei Wang, Jie Li, Zhitao Jiang","doi":"10.7150/jca.130206","DOIUrl":"10.7150/jca.130206","url":null,"abstract":"<p><p>The tumor suppressor genes BRCA1 and BRCA2 are essential for homologous recombination (HR) repair. Mutations in BRCA1/2 compromise HR repair efficacy, resulting in heightened susceptibility of tumor cells to poly (ADP-ribose) polymerase inhibitors (PARPi) via synthetic lethality. To date, several PARPi have been approved for BRCA-mutated and HR-deficient tumors, but acquired resistance and cumulative toxicity continue to limit their long-term clinical benefit. This narrative review offers an updated mechanistic model of PARPi action and categorizes resistance mechanisms by clinical relevance and evidentiary strength. Importantly, we distinguish between standard combination therapies in the PARPi-naïve setting and interventions explicitly tailored for PARPi-exposed or PARPi-resistant disease. Building on this distinction, we propose a biomarker-guided framework that links specific resistance phenotypes to appropriate specimen types, detection assays, and candidate interventions. Through this evidence-based clinical framework, we aim to clarify the current therapeutic landscape, improve data interpretation, and guide prospective trial design.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 9","pages":"1600-1614"},"PeriodicalIF":3.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573302/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronically Established ρ⁰ Cancer Cells Exhibit Shared Stemness-Associated and Aggressive Phenotypes Across Multiple Cancer Cell Lines.","authors":"Yu-Seon Han, Myeong-Eun Jegal, Su Yeon Lee, Joung-Sun Park, Yung-Jin Kim","doi":"10.7150/jca.138124","DOIUrl":"10.7150/jca.138124","url":null,"abstract":"<p><p>Chronically established mitochondrial DNA-depleted (ρ⁰) cancer cells may exhibit phenotypic changes beyond metabolic dysfunction; however, whether such changes are shared across different cancer types remains unclear. In this study, we generated chronically established ρ⁰ models from pancreatic, lung, and breast cancer cell lines and examined their common phenotypic features. Compared with their parental wild-type counterparts, the ρ⁰ cell lines exhibited increased proliferation, chemoresistance-related features, sphere-forming ability, wound closure, invasion-related phenotypes, and angiogenic activity, together with common morphological alterations. These changes were accompanied by VDAC1 upregulation and cytoskeletal remodeling. Pharmacologic treatment with VBIT-4 attenuated several of these phenotypes, whereas its effects on chemoresistance-related responses varied across cell lines. Collectively, these findings suggest that chronically established ρ⁰ cancer cells exhibit shared stemness-associated and aggressive phenotypes across multiple cancer cell lines, accompanied by VDAC1 upregulation and cytoskeletal remodeling.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 9","pages":"1615-1625"},"PeriodicalIF":3.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573307/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated Pan-Cancer, Single-Cell, and Spatial Transcriptomic Analyses Identify ZDHHC12 as a Biomarker Associated with Macrophage Infiltration and the Immune Landscape in Glioma.","authors":"Chao Zhang, Da Teng, Yu Wang, Shiqiang Hou, Wenjun Zhang, Ning Lin","doi":"10.7150/jca.136931","DOIUrl":"10.7150/jca.136931","url":null,"abstract":"<p><strong>Background: </strong>The tumor immune microenvironment (TME) critically influences cancer progression and therapeutic response. However, the pan-cancer expression landscape, prognostic relevance, and spatial distribution of ZDHHC12 remain incompletely characterized. This study investigated the prognostic value of ZDHHC12 and its associations with immune microenvironmental features and drug sensitivity.</p><p><strong>Methods: </strong>Data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets were used to evaluate ZDHHC12 expression and prognosis across cancer types. Immune infiltration analyses, single-cell RNA sequencing, and spatial transcriptomics were integrated to characterize the associations of ZDHHC12 with the cancer immunity cycle and the spatial architecture of glioma. Drug sensitivity and immunotherapy-related metrics were assessed using pharmacogenomic databases and computational prediction models.</p><p><strong>Results: </strong>ZDHHC12 was aberrantly expressed across multiple tumors and was associated with patient prognosis. Its expression was broadly correlated with immune cell recruitment- and activation-related signatures. In glioma, single-cell and spatial transcriptomic analyses showed enrichment of ZDHHC12 in monocyte/macrophage populations and spatial co-localization with BAK1, CD68, and CD163. ZDHHC12 expression was also associated with predicted drug sensitivity and immunotherapy-related metrics.</p><p><strong>Conclusion: </strong>ZDHHC12 may serve as a candidate pan-cancer prognostic biomarker. In glioma, its expression is associated with macrophage-enriched and immunosuppressive microenvironmental features. Functional studies are required to establish causality and determine its therapeutic relevance.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 9","pages":"1653-1670"},"PeriodicalIF":3.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573295/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic Value of the Prognostic Nutritional Index in Patients with Metastatic Melanoma.","authors":"Mustafa Sahbazlar, Hikmet Akar, Atike Pinar Erdogan, Ferhat Ekinci","doi":"10.7150/jca.136818","DOIUrl":"10.7150/jca.136818","url":null,"abstract":"<p><strong>Background: </strong>Prognostic outcomes vary considerably among patients with metastatic melanoma. We examined the association of the prognostic nutritional index (PNI), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) with overall survival in this patient population.</p><p><strong>Methods: </strong>We retrospectively evaluated 60 patients with metastatic melanoma treated at a single center. PNI was derived from serum albumin and absolute lymphocyte count. A cut-off of 52 was identified by ROC analysis and used to define the PNI groups. Overall survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression. PNI was entered into separate multivariable models with NLR or SII.</p><p><strong>Results: </strong>Overall survival was longer in patients with PNI ≥52 than in those with PNI <52 (log-rank <i>p</i> = 0.008). PNI, NLR, SII, and immunotherapy use were associated with OS in univariate Cox analysis. After multivariable adjustment, PNI remained significant in the model containing NLR (HR: 0.36, 95% CI: 0.15-0.85; <i>p</i> = 0.020) and in the model containing SII (HR: 0.37, 95% CI: 0.16-0.88; <i>p</i> = 0.024). Immunotherapy use was also independently associated with OS, whereas NLR and SII were not. PNI remained associated with OS when analyzed as a continuous variable (HR: 0.91, 95% CI: 0.84-0.98; <i>p</i> = 0.008). The AUC for PNI was 0.706 (95% CI: 0.551-0.833; <i>p</i> = 0.015).</p><p><strong>Conclusion: </strong>Higher PNI was independently associated with longer overall survival in this cohort of patients with metastatic melanoma. These findings support further investigation of PNI as a readily available prognostic marker, although validation in larger independent cohorts is needed.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 9","pages":"1576-1582"},"PeriodicalIF":3.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liquid Biopsy and Nonendoscopic Biomarkers for Precision Early Detection of Esophageal Cancer: Evidence, Risk Stratification and Translational Challenges.","authors":"Fangzheng Han, Huaimin Liu","doi":"10.7150/jca.140909","DOIUrl":"10.7150/jca.140909","url":null,"abstract":"<p><p>Esophageal cancer remains one of the most lethal malignancies worldwide, largely because most tumors are detected after symptoms develop. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) differ in epidemiology, precursor lesions and molecular biology, and therefore require subtype-specific early-detection pathways. This narrative critical review used a structured PubMed/MEDLINE search and classifies evidence by intended use: population risk triage for ESCC in high-incidence regions; targeted case finding for previously undiagnosed Barrett esophagus; surveillance and progression prediction in established Barrett esophagus; diagnostic evaluation of symptomatic or referred patients; and multicancer early-detection studies as indirect contextual evidence. We evaluate nonendoscopic cell-collection devices, cfDNA methylation and fragmentomics, mutation-based circulating tumor DNA assays, circulating RNA and extracellular vesicles, autoantibodies, metabolomic and microbiome signals, and clinical risk models. Although many clinically diagnosed or case-control series report high AUROC values, such estimates often overstate performance in asymptomatic populations, where low prevalence sharply limits positive predictive value. The most credible near-term role is calibrated, risk-stratified triage that concentrates endoscopy on individuals most likely to harbor early cancer or high-grade precursors. Increased detection yield, favorable modeling and implementation feasibility are not equivalent to clinical utility; utility requires evidence that biomarker-guided care improves meaningful outcomes at acceptable cost and harm. Integrated multiomic testing remains a proposed future strategy rather than a prospectively validated esophageal-cancer screening platform.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 9","pages":"1639-1652"},"PeriodicalIF":3.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573304/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cofilin/RhoA and CREB synergistically promote invasion and migration of polyploid giant cancer cells in colorectal cancer.","authors":"Yidi Ning, Kai Liu, Jing Xu, Liechen Ji, Shiwu Zhang","doi":"10.7150/jca.138960","DOIUrl":"10.7150/jca.138960","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is associated with high mortality and poor survival. Polyploid giant cancer cells (PGCCs) are a subset of cancer cells that drive tumor initiation and progression. In this study, high-concentration CoCl₂ treatment was used to induce Hct116 and LoVo cells to form PGCCs with daughter cells (PDCs), which exhibited enhanced invasion and migration capabilities. Cofilin expression was elevated in PDCs compared to that in the control cells. Mechanistically, the small ubiquitin-like modification (SUMOylation) of cofilin promoted its nuclear translocation and contributed to the aggressive phenotype of PDCs, with lysine 132 being identified as the key modification site mediated by tripartite motif-containing 28 (TRIM28). In addition, TRIM28 directly interacted with cofilin and inhibited its degradation, thereby increasing its stability. Nuclear cofilin facilitated RNA polymerase II-dependent upregulation of Ras homolog family member A (RhoA) transcription. RhoA enhanced nuclear accumulation of phosphorylated CREB (p-CREB), which further promoted cofilin transcription by binding to its promoter region. Cofilin knockdown inhibited the growth of xenograft tumors derived from Hct116 and LoVo PDCs. Regression analysis revealed that cofilin overexpression was associated with aggressive clinicopathological features in patients with CRC, although it did not significantly correlate with overall survival. Collectively, these findings revealed that cofilin is regulated by TRIM28-mediated SUMOylation and suggested that targeting the cofilin/RhoA/CREB axis may represent a promising therapeutic strategy for CRC.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 9","pages":"1583-1599"},"PeriodicalIF":3.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573303/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smoking-Associated Enrichment of CXCL13⁺ Tfh Cells and VCAM1⁺ Fibroblasts Is Linked to Tertiary Lymphoid Structure Formation in Lung Adenocarcinoma.","authors":"Yong Jun Choi, Chi Young Kim, Eun Young Kim, Sang Hoon Lee, Min Kyung Park, Yoon Soo Chang","doi":"10.7150/jca.138884","DOIUrl":"10.7150/jca.138884","url":null,"abstract":"<p><strong>Background: </strong>Smoking history is associated with improved immune checkpoint inhibitor treatment responses. We investigated smoking-associated differences in the tumor microenvironment (TME) of lung adenocarcinoma (LUAD) and identified biomarkers associated with tertiary lymphoid structure (TLS) formation.</p><p><strong>Methods: </strong>Single-cell RNA-sequencing datasets from tumors and matched adjacent normal tissues from five current smokers and five never-smokers with LUAD were integrated, and the T- and NK-cell compartments were analyzed in detail. Key findings were further evaluated using public LUAD scRNA-seq datasets and validated by immunofluorescence in formalin-fixed paraffin-embedded LUAD tissues using QuPath-based image analysis.</p><p><strong>Results: </strong>In current smokers, follicular helper T (Tfh) cells were enriched in the TME, whereas CD4⁺ tissue-resident memory T cells were reduced (R_O/E, median [interquartile range (IQR)]: 2.1 [1.5-5.7] vs. 1.0 [0.5-1.5], p=0.040; and 0.7 [0.6-1.1] vs. 1.7 [1.6-2.4], p<0.001, respectively). The Tfh cluster showed high expression of <i>CXCL13</i> and increased expression of <i>PDCD1</i> and <i>CTLA4</i>. Immunofluorescence confirmed increased CXCL13⁺CD4⁺ cells in current smokers (83.0 [10.0-218.5] vs. 10.0 [2.0-60.5] cells/0.25 mm², p<0.001). Gene set analysis showed enrichment of a B-cell chemotaxis signature in the Tfh cluster (normalized enrichment score, 1.693; adjusted p=0.023), and CXCL13⁺CD4⁺ T-cell density correlated with CD20⁺ B-cell density (Spearman ρ=0.445, p<0.001). Current smokers also showed greater TLS burden, with higher TLS counts and larger TLS areas, and had increased VCAM1⁺ fibroblast abundance (283.0 [118.5-580.5] vs. 98.5 [32.5-191.0] cells/0.25 mm², p<0.001), which strongly correlated with CD20⁺ cell density (Spearman ρ=0.766, p<0.001).</p><p><strong>Conclusions: </strong>Smoking-associated enrichment of CXCL13⁺CD4⁺ Tfh cells was associated with B-cell accumulation and TLS formation in LUAD. These findings identify the CXCL13⁺ Tfh-B-cell axis, together with VCAM1⁺ fibroblast-rich stromal niches, as potential biomarkers and therapeutic targets in LUAD.</p>","PeriodicalId":15183,"journal":{"name":"Journal of Cancer","volume":"17 9","pages":"1626-1638"},"PeriodicalIF":3.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13573297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148968881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}