Clinical & Experimental Metastasis最新文献

{"title":"THBS2: the key hub linking breast cancer stroma, immunity, and therapeutic response.","authors":"Xi Wan, Xinchen Zhao, Yao Lin, Shujie Yang, Han Dai, Yi Li, Xiaoshan Wang","doi":"10.1007/s10585-026-10419-9","DOIUrl":"10.1007/s10585-026-10419-9","url":null,"abstract":"<p><p>Thrombospondin-2 (THBS2) has emerged as a pivotal yet paradoxical regulator within the breast cancer (BC) tumor microenvironment (TME). This review synthesizes current evidence to elucidate its context-dependent duality and its potential as a novel therapeutic target. While THBS2 can function as a tumor suppressor by inhibiting angiogenesis, it more frequently exhibits pro-tumorigenic activities in aggressive subtypes like triple-negative breast cancer (TNBC). Here, THBS2, predominantly secreted by cancer-associated fibroblasts, drives metastasis by activating key oncogenic pathways including PI3K/AKT, Notch, and Wnt/β-catenin, thereby promoting epithelial-mesenchymal transition (EMT) and stemness. Its expression and functional output are further complicated by competitive endogenous RNA (ceRNA) network regulation, explaining contradictory clinical associations. Crucially, THBS2 is a key architect of an immunosuppressive \"cold\" TME. It constructs dual barriers: a physical barrier through extracellular matrix remodeling that impedes T-cell infiltration, and a chemical barrier by potentially suppressing CD36⁺ T-cell function. Consequently, therapeutic inhibition of THBS2 presents a promising integrative \"cold-to-hot\" conversion strategy. By simultaneously dismantling stromal architecture and alleviating local immune suppression, targeting THBS2 could enhance T-cell trafficking and reactivate anti-tumor immunity, potentially overcoming resistance to current immunotherapies. Future research must adopt a network-based approach to decipher THBS2's contextual roles and translate its targeting into effective combination strategies for advanced breast cancer.</p>","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 5","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148788851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Cullin 3 overexpression inhibits lung cancer metastasis and is associated with survival of lung adenocarcinoma.","authors":"Jiayu Zhou, Shizhen Zhang, Yong Xu, Weiwen Ye, Zhijun Li, Zhoumiao Chen, He Zhengfu","doi":"10.1007/s10585-026-10414-0","DOIUrl":"10.1007/s10585-026-10414-0","url":null,"abstract":"","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148720715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Radiomics for risk stratification in brain metastases: potential in melanoma brain metastases.","authors":"Johanna Heugenhauser, Sabrina Herbst, Tamara Drucks, Christoph Scherfler, Tadeja Urbanic Purkart, Eva Maria Hassler, Richard Partl, Marlene Leoni, Kariem Mahdy Ali, Sarah Iglseder, Christian Freyschlag, Stephanie Mangesius, Astrid Grams, Meinhard Nevinny-Stickel, Martha Nowosielski","doi":"10.1007/s10585-026-10422-0","DOIUrl":"10.1007/s10585-026-10422-0","url":null,"abstract":"<p><p>The identification of quantitative non-invasive imaging biomarkers, including radiomics, may complement molecular characterization and thereby improve clinical management of neuro-oncological patients. We aimed to identify imaging predictors with improved performance over clinical parameters to stratify patients with brain metastases into high and low-risk groups for overall survival (OS). 422 patients recruited by two neuro-oncological centers were included with first diagnosis of brain metastases from different primary tumors. From each patient, 15 clinical parameters and a total of 321 radiomic features extracted from cerebral MRI were employed in prediction models to classify patients into low- and high-risk groups for OS. The best performing model was a bootstrap aggregating model including only clinical features (test set: macro F-1 = 0.62, accuracy = 0.72), while the combined and radiomic datasets led to poorer results (test set: macro F-1 = 0.60, accuracy = 0.67; test set: macro F-1 = 0.62, accuracy = 0.52, respectively). However, in the subgroup of melanoma patients (n = 54), the radiomic dataset showed better predictive power over clinical and combined dataset (test set: macro F-1 score = 0.71, accuracy = 0.77). 80% and 67% of melanoma patients were correctly classified into the low- and the high-risk group for OS, respectively. Clinical features remained the strongest predictors of risk across patients with brain metastases from different primary tumors. Although, in melanoma patients, radiomic features provided better prediction of the survival outcome compared to clinical parameters alone.</p>","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13451392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148683553","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":"Treatment patterns and outcomes of second/third-line therapy in advanced non-small cell lung cancer with actionable genomic alterations (RECAP).","authors":"Hanxiao Chen, Xiangjiao Meng, Ling Cai, Wei Lei, Yu Tang, Xi Shi, Leilei Ma, Jun Zhao","doi":"10.1007/s10585-026-10417-x","DOIUrl":"10.1007/s10585-026-10417-x","url":null,"abstract":"<p><p>Treatment choices for metastatic non-small-cell lung cancer (NSCLC) after first-line targeted therapy progression are heterogeneous. This study aimed to characterize real-world treatment patterns and outcomes of advanced NSCLC harboring actionable genomic alterations (AGAs) in second- (2 L) or third-line (3 L) settings. This retrospective cohort study across six Chinese centers included stage IV NSCLC patients with confirmed AGAs. Therapies were divided into six categories: targeted monotherapy (T), targeted combinations (T+), chemotherapy monotherapy (C), chemotherapy combinations (C+), anti-angiogenic monotherapy (A), and other regimens (O). The primary outcome was the treatment pattern. Secondary outcomes included biomarker testing and effectiveness. A total of 658 patients were enrolled, with the majority harboring EGFR mutations (n = 590, 89.7%). In the 2 L-enrolled group (n = 602), T use declined from 75.3% in the 1 L setting to 49.3% in 2 L, while utilization of A + C increased to 16.5%. Within the EGFR-mutant subgroup, therapeutic sequences were highly dependent on 1 L TKI generation and T790M resistance status. Over half (51.1%) of T790M-negative patients continued T in 2 L following progression on 1 L first- or second-generation TKIs. Among the 3 L-enrolled patients (n = 56), A + C (35.7%) and C (14.3%) were predominant. The overall median real-world progression-free survival for the 2 L-enrolled group was 7.4 months in the 2 L setting (7.5 months for the EGFR-mutant subgroup) and 5.4 months in 3 L. This multicenter real‑world cohort predominantly comprised patients with EGFR‑mutant NSCLC, with smaller numbers of other AGA subtypes. Targeted therapies remain the cornerstone of later-line advanced NSCLC management. The prevalent real-world reliance on continued TKI therapy, even in T790M-negative patients, highlights the clinical dilemma of limited post-resistance options and the need to integrate emerging novel therapeutics.</p>","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13423968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618735","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":"CYP4B1 inhibits lung adenocarcinoma metastasis by downregulating slug transcription via Sp1.","authors":"Sijia Wang, Yijie Liu, Yuan Yu, Shuwei Ren, Weiwei Lin, Kemeng Qiang, Haishan Huang, Honglei Jin","doi":"10.1007/s10585-026-10421-1","DOIUrl":"10.1007/s10585-026-10421-1","url":null,"abstract":"<p><p>Lung adenocarcinoma (LUAD), the most prevalent subtype of non-small cell lung cancer, is characterized by strong metastatic potential and poor survival rates. Here, we identified CYP4B1 as a potential biomarker associated with LUAD progression. Through immunohistochemical analyses, we observed that CYP4B1 expression levels were significantly downregulated in tumors. Clinically, low CYP4B1 expression was correlated with shorter disease-free survival in LUAD patients, but not in those with lung squamous cell carcinoma. Functional experiments, including transwell and soft agar assays, demonstrated that CYP4B1 overexpression suppressed the migration and invasion capabilities of LUAD cells without influencing their proliferation, acting through Sp1-mediated Slug downregulation. These findings establish the CYP4B1/Slug axis as a LUAD-associated regulatory mechanism and highlight its potential as a therapeutic target, underscoring the importance of molecular stratification in precision oncology.</p>","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic review of extracellular vesicle-based liquid biopsy for leptomeningeal metastasis: current evidence and future directions.","authors":"Shrinit Babel, Suman Baral, Syed R H Peeran, Gandham E Jonathan","doi":"10.1007/s10585-026-10420-2","DOIUrl":"10.1007/s10585-026-10420-2","url":null,"abstract":"<p><p>Leptomeningeal Metastasis (LM) is a catastrophic complication of systemic malignancies with poor prognosis and significant diagnostic challenges. Extracellular vesicle (EV)-based liquid biopsy is an emerging technology that may improve the detection, prognosis, and therapeutic monitoring for LM. This systematic review aims to critically appraise and synthesize existing evidence on the use of EV-derived biomarkers from cerebrospinal fluid (CSF) or serum for the diagnosis, prognosis, and therapeutic monitoring of LM. A systematic search of PubMed, ScienceDirect, Semantic Scholar, and Google Scholar was conducted up to January 2025. Eligible studies evaluated EV-associated molecular biomarkers (microRNAs or proteins) in LM patients using CSF or serum samples. Data extraction included study design, sample source, EV isolation method, biomarker type, validation method, and diagnostic/prognostic relevance. Risk of bias was assessed using QUADAS-2. Ten studies met inclusion criteria, encompassing EV miRNA and proteomic profiling in LM, primarily from non-small cell lung cancer (NSCLC) and medulloblastoma. miR-21 consistently correlated with poor prognosis and therapy resistance. Novel candidates such as miR-183-5p demonstrated high diagnostic accuracy (AUC 1.0 in a discovery cohort), targeting PTEN pathways. EV-derived proteins including fibronectin-1 (FN1), transketolase (TKT), and complement C2 also showed strong discriminative potential. Heterogeneity in EV isolation techniques and small sample sizes limited meta-analysis feasibility. EV-based liquid biopsy holds cautious promise as a minimally invasive tool for LM diagnosis, prognosis, and therapeutic monitoring. Larger, multicenter studies with standardized protocols are required to validate these findings and facilitate clinical translation.</p>","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13391725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148548037","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":"Luteolin inhibits hyperglycemia-induced epithelial-mesenchymal transition and malignant progression in gastric cancer via targeting AKR1B1-mediated glucose metabolism.","authors":"Qin He, Feibao Tao, Xiaowen Wen, Liang Zhu, Xuxing Ye","doi":"10.1007/s10585-026-10418-w","DOIUrl":"10.1007/s10585-026-10418-w","url":null,"abstract":"<p><p>Gastric cancer (GC) is a very aggressive cancer with a high potential for metastasis. A naturally occurring flavonoid, luteolin (Lut) has metabolic regulation and anti-cancer properties. This work investigates whether Lut modulates glucose metabolism and targets AKR1B1 to prevent the epithelial-mesenchymal transition (EMT) in GC. Lut was used to treat human GC cell lines that were grown in both normal and high-glucose environments. Western blotting and qPCR were used to assess the expression levels of EMT markers and AKR1B1. The CCK-8 assay, the scratch assay, and the Transwell assay were used to measure cell movement, invasion, and proliferation, respectively. Metabolic flux analysis was used to measure fructose and lactate generation in order to assess glycolytic activity. We carried out AKR1B1 overexpression and knockdown experiments to elucidate the functional involvement of AKR1B1 in the action of Lut. In order to fully assess the anticancer effects of Lut and its underlying mechanisms, a high-glucose paradigm in nude mice was developed for in vivo validation. AKR1B1 expression was markedly elevated in GC cells under high-glucose circumstances, and this was accompanied by increased glycolytic activity. At the same time, the cells showed signs of EMT, including enhanced migratory and invasion capacities. Subsequent research showed that Lut therapy substantially alleviated anomalies in glucose metabolism by drastically suppressing AKR1B1 expression, downregulating important glycolytic enzymes, and reducing the generation of fructose and lactate. Additionally, by boosting E-cadherin expression, lowering vimentin and N-cadherin levels, and preventing cell migration and invasion, luteolin dramatically corrected high-glucose-induced EMT. The inhibitory effects of luteolin on glycolysis and EMT were largely offset by AKR1B1 overexpression, according to functional experiments; on the other hand, inhibition of AKR1B1 considerably reduces AKT pathway activation, which suppresses the malignant phenotype of gastric cancer cells. Together, these findings show how important AKR1B1 is to this regulatory axis. According to these results, luteolin inhibits high-glucose-induced metabolic reprogramming and EMT in gastric cancer cells via acting on AKR1B1, which lowers the cells' capacity for metastasis. Lut may reduce the metabolic dysregulation brought on by hyperglycemia by blocking AKR1B1, which in turn prevents GC cells from undergoing the epithelial-mesenchymal transition. This discovery highlights Lut as a potential metabolic therapeutic drug and offers mechanistic insight into the evolution of gastric cancer caused by hyperglycemia.</p>","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"XRN2, governed by RNA-binding protein PTBP3, promotes the invasiveness of esophageal squamous cell carcinoma.","authors":"Chenglai Dong, Deqi Zhu, Jincao Zhang, Shaoyin Gan, Jia Zhao, Chunlin Li, Bin Li","doi":"10.1007/s10585-026-10415-z","DOIUrl":"10.1007/s10585-026-10415-z","url":null,"abstract":"<p><p>Metastasis contributes to treatment failure and poor prognosis of esophageal squamous cell carcinoma (ESCC) patients. The 5'-3' exoribonuclease 2 (XRN2) is related to the pathogenesis and progression of various malignancies through its roles in transcription termination and metastasis promotion, but its function in ESCC remains unclear. Bioinformatic analysis showed that XRN2 was significantly overexpressed in ESCC tissues and was identified as a risk factor for ESCC patients. The analysis of our own cohort confirmed that XRN2 expression was overexpressed and significantly correlated with cancer stage in patients (P = 0.0100). Gain- and loss- of function analyses revealed that XRN2 promoted ESCC cell growth, migration and invasion capabilities, as well as experimental lung colonization foci. Interestingly, we found that the RNA level of XRN2 was upregulated by the RNA-binding protein polypyrimidine tract binding protein 3 (PTBP3). Specifically, PTBP3 bound to CUUUC motifs of the 3'UTR of XRN2, prolonging the half-life of XRN2 RNA. PTBP3 was found to be significantly overexpressed in ESCC, where its expression level correlated with tumor stage (P = 0.0164) and tumor size (P = 0.0495), positioning it as a risk factor for ESCC patients. PTBP3 upregulation promoted ESCC cell growth, migration, and invasion in vitro and in vivo. Notably, knockdown of XRN2 reversed the tumor promotion effects induced by PTBP3 overexpression. Collectively, our data reveal a novel function of XRN2 in ESCC metastasis and the critical roles of the PTBP3/XRN2 axis in ESCC metastasis, highlighting its promise as a novel therapeutic target in ESCC.</p>","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148387400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety evaluation of TOPAZ-1 and KEYNOTE-966 regimens in metastatic biliary tract cancer: a systematic review and meta-analysis.","authors":"Elsa Vitale, Lorenza Maistrello, Francesco Ciccimarra, Deniz Can Guven, Taha Koray Sahin, Fernando Sabino Marques Monteiro, Raffaele de Luca, Matteo Scaramuzzi, Sabina Delcuratolo, Oronzo Brunetti, Alessandro Rizzo, Giovanni Brandi","doi":"10.1007/s10585-026-10416-y","DOIUrl":"10.1007/s10585-026-10416-y","url":null,"abstract":"<p><p>The addition of immunotherapy to chemotherapy has improved prognosis of metastatic biliary tract cancer (BTC). The present systematic review aimed to assess frequency of treatment-emergent adverse events (TEAEs) among metastatic BTC patients receiving first-line immune checkpoint inhibitors (ICIs) plus chemotherapy in the two practice-changing TOPAZ-1 and KEYNOTE-966 clinical trials. The present systematic review and meta-analysis was recorded in the PROSPERO register with no. CRD420251137398. Incidence of TEAEs in patients receiving ICIs plus chemotherapy and in patients treated with placebo plus chemotherapy was collected. A total of two studies were included in these analyses including 1754 patients, comprising 1743 observations and 193 events for Grade 1/2 and 650 events for Grade ≥ 3. The risk of several TEAEs did not significantly differ between patients receiving chemoimmunotherapy versus those treated with chemotherapy alone. The present meta-analysis further confirms the tolerable safety profile of TOPAZ-1 and KEYNOTE-966 regimens as first-line therapy in advanced BTC. Future research should focus on identifying risk factors for TEAEs and develop prophylactic strategies to mitigate this risk without blunting antitumor efficacy. By improving our understanding and management of TEAEs, we might maximize the clinical benefits of ICIs and minimize harm, ultimately enhance clinical outcomes for BTC patients.</p>","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 4","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148344090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NF1 mutation may be associated with lung-tropic metastasis in cutaneous melanoma: a genomic analysis of 520 patients.","authors":"Doğancan Akpalamut","doi":"10.1007/s10585-026-10413-1","DOIUrl":"10.1007/s10585-026-10413-1","url":null,"abstract":"<p><strong>Background: </strong>Metastatic organotropism in cutaneous melanoma remains incompletely understood at the genomic level. While prior work has linked BRAF and NRAS mutations to organ-specific metastasis patterns, the role of NF1 has not been systematically evaluated. We investigated whether NF1 mutation is specifically associated with lung metastasis in cutaneous melanoma.</p><p><strong>Methods: </strong>We analyzed 520 patients with metastatic cutaneous melanoma from the MSK-MET cohort, comparing 258 with documented lung metastasis to 262 without. Gene-level enrichment was tested across 118 genes meeting a 5% mutation-frequency threshold on the shared MSK-IMPACT panel, with Benjamini-Hochberg false discovery correction. Robustness was evaluated by panel-stratified, era-stratified, Cochran-Mantel-Haenszel, and bias-corrected bootstrap analyses. Organ specificity was tested across 12 metastatic sites. Multivariable logistic regression adjusted for tumor mutational burden (TMB), age, and sequencing panel. Overall survival was analyzed by Cox proportional hazards modeling.</p><p><strong>Results: </strong>NF1 was the single gene crossing the primary significance threshold (OR 2.11, 95% CI 1.40-3.21; p = 1.89 × 10^-4; q = 0.022), with 34.9% mutation frequency in lung-metastatic versus 20.2% in non-lung-metastatic tumors. The association remained significant after multivariable adjustment (adjusted OR 1.81, 95% CI 1.13-2.92; p = 0.014) and was consistent across all four robustness analyses (OR range 2.10-2.31). The enrichment persisted within the pure NF1 subtype (BRAF/RAS-wild-type; OR 1.93, 95% CI 1.15-3.29; p = 0.010), confirming it is intrinsic to NF1 loss rather than to co-occurring activating genes. Enrichment was anatomically restricted to the lung, with significant depletion at adrenal and intra-abdominal sites. NF1 mutations showed a loss-of-function dominant, hotspot-free distribution. NF1-mutant tumors carried approximately two-fold higher TMB than wild-type counterparts (median 43.2 vs. 18.6 mut/Mb; p < 0.001), with the majority exceeding the pembrolizumab-eligible threshold.</p><p><strong>Conclusions: </strong>NF1 mutation is the strongest gene-level correlate of lung-selective metastasis in cutaneous melanoma. The NF1-mutant subtype may represent a dual-biomarker population and could warrant both pulmonary surveillance and prospective evaluation for immunotherapy.</p>","PeriodicalId":10267,"journal":{"name":"Clinical & Experimental Metastasis","volume":"43 3","pages":""},"PeriodicalIF":3.7,"publicationDate":"2026-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148194492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}