Cancer letters最新文献

{"title":"Artificial intelligence in predicting efficacy and toxicity of Immunotherapy: Applications, challenges, and future directions","authors":"Qiang Wen ,&nbsp;Liang Qiu ,&nbsp;Chenhui Qiu ,&nbsp;Keying Che ,&nbsp;Renya Zeng ,&nbsp;Xi Wang ,&nbsp;Pingdong Cao ,&nbsp;Lei Xing ,&nbsp;Zhe Yang ,&nbsp;Jinming Yu","doi":"10.1016/j.canlet.2025.217881","DOIUrl":"10.1016/j.canlet.2025.217881","url":null,"abstract":"<div><div>Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, becoming a standard approach for various tumor types. Consequently, accurately predicting their efficacy has become crucial in clinical practice. Artificial intelligence (AI) has emerged as a powerful tool for extracting meaningful insights from complex clinical datasets, showing immense potential to transform medical decision-making. Therefore, the integration of AI techniques into immunotherapy facilitates the development of predictive models for immunotherapeutic efficacy based on radiological, genomic, and pathological data, ultimately refining the precision treatment of tumors. In this review, we systematically summarize the application of AI in predicting the efficacy of ICIs, and briefly address the challenges and future directions in this field.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"630 ","pages":"Article 217881"},"PeriodicalIF":9.1,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of FTSJ3 promotes R-loop-associated DNA damage and facilitates chemosensitivity in lung cancer cells","authors":"Hongchengcheng Chen ,&nbsp;Guihui Yu ,&nbsp;Haodong Lin ,&nbsp;Xiao Albert Zhou ,&nbsp;Jiansong Liu ,&nbsp;Haoyun Liu ,&nbsp;Yefei Luo ,&nbsp;Kaiqi Cheng ,&nbsp;Zuchao Mao ,&nbsp;Yujie Ma ,&nbsp;Jun Wang ,&nbsp;Kezhong Chen ,&nbsp;Jiadong Wang ,&nbsp;Yun Li","doi":"10.1016/j.canlet.2025.217877","DOIUrl":"10.1016/j.canlet.2025.217877","url":null,"abstract":"<div><div>R-loop accumulation has emerged as a critical factor that induces DNA damage and compromises genomic integrity. However, the regulatory mechanisms governing the R-loop-induced DNA damage remain unclear. Here, FTSJ3 was determined to be a pivotal regulator of R-loop homeostasis and genomic stability. We demonstrated that FTSJ3 was specifically recruited to R-loop structures, where it prevented DNA damage by suppressing excessive R-loop formation. FTSJ3 expression was significantly upregulated in multiple cancer types, and its elevated expression levels correlated with unfavorable survival in patients with lung adenocarcinoma (LUAD). FTSJ3 depletion increased R-loop-dependent DNA damage. Inhibiting FTSJ3 expression sensitized lung cancer cells to cisplatin both <em>in vitro</em> and <em>in vivo</em>. FTSJ3 could be a genome guardian that limits R-loop-associated damage, suggesting its potential role as a cancer intervention therapeutic target and a predictive biomarker for chemotherapy responsiveness.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"631 ","pages":"Article 217877"},"PeriodicalIF":9.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing chromosome instability reveals its association with lipid-associated macrophages and clonal evolution of lymph node metastasis in esophageal squamous cell carcinoma","authors":"Wei Dai ,&nbsp;Josephine Mun-Yee Ko ,&nbsp;Valen Zhuoyou Yu ,&nbsp;Zhaozheng Hou ,&nbsp;Larry Ka-Yue Chow ,&nbsp;Michael King Yung Chung ,&nbsp;Kazi Anisha Islam ,&nbsp;Bianca Hoi-yan Ng ,&nbsp;Carissa Wing-Yan Wong ,&nbsp;Ka-Kiu Leung ,&nbsp;Cancan Chen ,&nbsp;Ian Yu Hong Wong ,&nbsp;Simon Ying-Kit Law ,&nbsp;Anthony Wing-Ip Lo ,&nbsp;Alfred King-Yin Lam ,&nbsp;Maria Li Lung","doi":"10.1016/j.canlet.2025.217874","DOIUrl":"10.1016/j.canlet.2025.217874","url":null,"abstract":"<div><div>Esophageal cancer is an aggressive cancer, and metastasis is one of the major factors contributing to treatment failure, leading to poor clinical outcomes. Chromosome instability (CIN) is frequently observed in esophageal squamous cell carcinoma (ESCC). However, the functional impact of CIN is not well studied in ESCC metastasis. We aim to study the role and underlying mechanisms of CIN in lymph node (LN) metastasis. Integrated analysis was performed using single-cell RNA sequencing data with matched whole-exome sequencing in primary ESCC, genomic sequencing in ESCC organoids and clinical specimens, and spatial protein profiling to characterize CIN and relevant tumor immune microenvironment (TIME) associated with LN metastasis. CIN in primary ESCC <strong>i</strong>s significantly associated with LN metastasis at diagnosis, particularly in those patients with homologous recombination deficiency and use of alternative end joining (alt-EJ). Primary CIN ESCC exhibited increased epithelial-mesenchymal transition (EMT), hypoxia, angiogenesis, RNA metabolism, and heat stress, associated with a strong metastatic potential. Although CIN ESCC ha<strong>s</strong> elevated neoantigen loads, its TIME was enriched for immunosuppressive lipid-associated tumor-associated macrophages (LA-TAMs). Secreted phosphoprotein 1 (SPP1) plays a key role in mediating the communications of CIN ESCC cells and LA-TAMs. In LN metastases, structural CIN (sCIN) with retrotransposon insertion and reactivation is important for ESCC clonal evolution and cell proliferation, associated with increased LA-TAMs infiltration and poor overall patient survival. ESCC with high CIN has a strong metastatic potential. Our findings reveal a novel link between error-prone DSB repair pathways and LA-TAMs through CIN in LN metastasis.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217874"},"PeriodicalIF":9.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144281087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Energetics of whole genome doubling and genomic instability.","authors":"Richard J Beck, Vural Tagal, Samirkumar Amin, Samuel F Bakhoum, Carlo C Maley, Roel G W Verhaak, Ana P Gomes, Noemi Andor","doi":"10.1016/j.canlet.2025.217878","DOIUrl":"10.1016/j.canlet.2025.217878","url":null,"abstract":"<p><p>Whole genome doubling (WGD) is among the most prevalent genomic alterations in cancer, present in approximately one third of patients at the time of diagnosis. WGD provides cancer cells with a selective advantage, by protecting against mutations in haploinsufficient genes or buffering deleterious mutations. Factors which negatively select against the WGD state are largely unexplored. Here, we review evidence indicating that cells with WGD are more sensitive to resource restriction than their non-WGD counterparts. We hypothesize that differences in energy access across tissue sites explain differences in cancer ploidy and aneuploidy at the time of detection. By shedding light on the energetic constraints that influence cancer ploidy and aneuploidy, this perspective highlights a critical yet underexplored area of cancer research.</p>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":" ","pages":"217878"},"PeriodicalIF":9.1,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isocucurbitacin B inhibits gliomas through the promotion of anoikis by targeting caveolin 1","authors":"Mingyu Han ,&nbsp;Jianning Yang ,&nbsp;Pingting Chen ,&nbsp;Sui Li ,&nbsp;Hailin Tang ,&nbsp;Huali Fan ,&nbsp;Yuhan Wang ,&nbsp;Xue Li ,&nbsp;Weiwei Pan ,&nbsp;Vasili Koutouratsas ,&nbsp;Zijin Zhao ,&nbsp;Fu Peng","doi":"10.1016/j.canlet.2025.217873","DOIUrl":"10.1016/j.canlet.2025.217873","url":null,"abstract":"<div><div>Gliomas, known for their aggressive nature, high recurrence rates, and resistance to conventional therapies, require the development of novel treatment strategies. This study emphasizes the critical role of caveolin 1 (CAV1) in glioma progression and highlights the potent anti-glioma effects of isocucurbitacin B. The compound effectively inhibits glioma cell proliferation, invasion, migration, and epithelial-mesenchymal transition, while also inducing G2/M phase arrest and promoting apoptosis. Further analysis revealed that isocucurbitacin B promotes anoikis, a form of cell death induced by detachment, by downregulating CAV1. Notably, isocucurbitacin B directly binds to CAV1, confirmed by cellular thermal shift assays and microscale thermophoresis, positioning CAV1 as a key therapeutic target. Additionally, isocucurbitacin B activates the BKCa calcium channel, resulting in increased intracellular Ca²⁺ and reduced pH, establishing a novel connection between calcium dynamics and anoikis. Overexpression of CAV1 inhibited anoikis, blocking apoptosis and promoting migration, while decreased CAV1 expression facilitated anoikis and significantly reduced glioma cell proliferation and motility. <em>In vivo</em> experiments using zebrafish patient-derived xenografts and orthotopic glioblastoma models further demonstrated that isocucurbitacin B effectively suppresses tumor growth by downregulating CAV1. These findings underscore the multifaceted anti-glioma potential of isocucurbitacin B and highlight CAV1 as a crucial mediator of anoikis and a promising therapeutic target in glioma treatment.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"629 ","pages":"Article 217873"},"PeriodicalIF":9.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of tumor microenvironment and immune cell crosstalk in triple-negative breast cancer (TNBC): Emerging therapeutic opportunities","authors":"Hussein Sabit ,&nbsp;Amro Adel ,&nbsp;Mariam M. Abdelfattah ,&nbsp;Rehab M. Ramadan ,&nbsp;Mahmoud Nazih ,&nbsp;Shaimaa Abdel-Ghany ,&nbsp;Ahmed El-hashash ,&nbsp;Borros Arneth","doi":"10.1016/j.canlet.2025.217865","DOIUrl":"10.1016/j.canlet.2025.217865","url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by its lack of estrogen, progesterone, and HER2 receptors, leading to limited treatment options and poor prognosis. This review synthesizes current research on the tumor microenvironment (TME) and immune cell crosstalk in TNBC to identify emerging therapeutic opportunities. The TME in TNBC is a complex ecosystem comprising immune cells, fibroblasts, and extracellular matrix components, which significantly influence tumor growth and metastasis. Single-cell RNA sequencing reveals T-cell heterogeneity and identifies prognostic genes. Regulatory T cells (Tregs) play a key role in immunosuppression, with thymidine kinase-1 (TK1) identified as a potential therapeutic target. MUC1-C and CXCL9 modulate the TME, impacting T-cell depletion and macrophage differentiation. Spatial analysis highlights the importance of cell-to-cell interactions in predicting recurrence. Epithelial-mesenchymal transition (EMT) and thermogenesis also influence the TME, while epigenetic modifications, such as HDAC inhibition, can induce pyroptosis and enhance immune cell recruitment. Integrating genomic information with TME analysis is crucial for developing personalized treatments, considering racial disparities in immune infiltration. Emerging therapies targeting immune checkpoints, modulating Treg activity, and inducing pyroptosis hold promise for improving TNBC patient outcomes. Future research should focus on multi-omics data, spatial transcriptomics, and patient-derived models to refine therapeutic interventions.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217865"},"PeriodicalIF":9.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Analysis and characterization of extrachromosomal circular DNA in prostate cancer: Potential biomarker discovery from urine, plasma, and tumor samples","authors":"Mingxin Zhang ,&nbsp;Zhe Xu ,&nbsp;Yuxuan Cao ,&nbsp;Chengwen Gao ,&nbsp;Guangdi Chu ,&nbsp;Guofeng Xia ,&nbsp;Yuqing Tian ,&nbsp;Nian Liu ,&nbsp;Anqi Wang ,&nbsp;Weimin Ma ,&nbsp;Pengcheng Yang ,&nbsp;Mingxuan Wu ,&nbsp;Yihong Lian ,&nbsp;Xiangzhong Zhao ,&nbsp;Qian Zhang ,&nbsp;Peng Han ,&nbsp;Yonghua Wang ,&nbsp;Zhiqiang Li ,&nbsp;Haitao Niu","doi":"10.1016/j.canlet.2025.217875","DOIUrl":"10.1016/j.canlet.2025.217875","url":null,"abstract":"<div><div>Extrachromosomal circular DNA (eccDNA) may contribute to genomic rearrangements and tumor heterogeneity, playing a role in cancer development and progression. This study evaluates eccDNA as a biomarker for prostate cancer by characterizing its profiles in urine, plasma, and tumor tissues from patients at different disease stages. We studied 49 prostate cancer patients (23 early-stage; 26 late-stage, including 19 with metastasis), 23 patients with prostatitis, and 21 healthy individuals. EccDNA was extracted from plasma, urine, and tumor tissues using the Circle-Map workflow. We analyzed eccDNA abundance, genomic origin, GC content, length distribution, and repetitive sequence content. Differences among these groups were assessed with the Wilcoxon rank-sum test, and five machine learning models classified cancer vs. non-cancer based on eccDNA features. Significant variations in eccDNA levels were observed among sample types and disease states. Prostate cancer patients exhibited higher eccDNA abundance in tumor tissues compared to plasma and urine samples. Metastatic patients had significantly elevated plasma eccDNA levels compared to nonmetastatic patients and controls. Tumor-derived eccDNA showed higher GC content and distinct length distributions. Shared eccDNA molecules across tissue types suggest common origins and potential systemic roles in cancer progression. Classification models achieved strong performance, especially in plasma, where a Neural Network model reached an AUC of 0.91, and in urine, where a Random Forest model reached 0.77. Limitations include the relatively small cohort size and the need for functional studies to clarify eccDNA's role in cancer biology. This study highlights eccDNA's potential as a noninvasive biomarker for prostate cancer diagnosis and monitoring. The distinct eccDNA profiles across urine, plasma, and tumor tissues reflect disease states and progression, suggesting its utility in clinical applications.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217875"},"PeriodicalIF":9.1,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-based radiomic features predict outcomes and the added benefit of chemoimmunotherapy over chemotherapy in extensive stage small cell lung cancer: A multi-institutional study","authors":"Mohammadhadi Khorrami ,&nbsp;Pushkar Mutha ,&nbsp;Cristian Barrera ,&nbsp;Vidya S. Viswanathan ,&nbsp;Fatemeh Ardeshir-Larijani ,&nbsp;Prantesh Jain ,&nbsp;Kristin Higgins ,&nbsp;Anant Madabhushi","doi":"10.1016/j.canlet.2025.217872","DOIUrl":"10.1016/j.canlet.2025.217872","url":null,"abstract":"<div><div>Small cell lung cancer (SCLC) is aggressive with poor survival outcomes, and most patients develop resistance to chemotherapy. No predictive biomarkers currently guide therapy. This study evaluates radiomic features to predict PFS and OS in limited-stage SCLC (LS-SCLC) and assesses PFS, OS, and the added benefit of chemoimmunotherapy (CHIO) in extensive-stage SCLC (ES-SCLC). A total of 660 SCLC patients (470 ES-SCLC, 190 LS-SCLC) from three sites were analyzed. LS-SCLC patients received chemotherapy and radiation, while ES-SCLC patients received either chemotherapy alone or CHIO. Radiomic and quantitative vasculature tortuosity features were extracted from CT scans. A LASSO-Cox regression model was used to construct the ES- Risk-Score (ESRS) and LS- Risk-Score (LSRS). ESRS was associated with PFS in training (HR = 1.54, adj. P = .0013) and two independent validation sets (HR = 1.32, adj. P = .0001; HR = 2.4, adj. P = .0073) and with OS in training (HR = 1.37, adj. P = .0054) and validation sets (HR = 1.35, adj. P &lt; .0006; HR = 1.6, adj. P &lt; .0085) in ES-SCLC patients treated with chemotherapy. High-risk patients had improved PFS (HR = 0.68, adj. P &lt; .001) and OS (HR = 0.78, adj. P = .026) with CHIO. LSRS was associated with PFS in training and two independent validation sets (HR = 1.9, adj. P = .007; HR = 1.4, adj. P = .0098; HR = 2.1, adj. P = .028) in LS-SCLC patients receiving chemoradiation. Radiomics is prognostic for PFS and OS and predicts chemoimmunotherapy benefit in high-risk ES-SCLC patients.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217872"},"PeriodicalIF":9.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RCMIX model based on pre-treatment MRI imaging predicts T-downstage in MRI-cT4 stage rectal cancer","authors":"Feiyu Bai ,&nbsp;Leen Liao ,&nbsp;Yuanling Tang ,&nbsp;Yihang Wu ,&nbsp;Zhangjie Wang ,&nbsp;Hengyu Zhao ,&nbsp;Jingming Huang ,&nbsp;Xin Wang ,&nbsp;Peirong Ding ,&nbsp;Xiaojian Wu ,&nbsp;Zerong Cai","doi":"10.1016/j.canlet.2025.217871","DOIUrl":"10.1016/j.canlet.2025.217871","url":null,"abstract":"<div><div>Neoadjuvant therapy (NAT) is the standard treatment strategy for MRI-defined cT4 rectal cancer. Predicting tumor regression can guide the resection plane to some extent. Here, we covered pre-treatment MRI imaging of 363 cT4 rectal cancer patients receiving NAT and radical surgery from three hospitals: Center 1 (n = 205), Center 2 (n = 109) and Center 3 (n = 52). We propose a machine learning model named RCMIX, which incorporates a multilayer perceptron algorithm based on 19 pre-treatment MRI radiomic features and 2 clinical features in cT4 rectal cancer patients receiving NAT. The model was trained on 205 cases of cT4 rectal cancer patients, achieving an AUC of 0.903 (95 % confidence interval, 0.861–0.944) in predicting T-downstage. It also achieved AUC of 0.787 (0.699–0.874) and 0.773 (0.646–0.901) in two independent test cohorts, respectively. cT4 rectal cancer patients who were predicted as Well T-downstage by the RCMIX model had significantly better disease-free survival than those predicted as Poor T-downstage. Our study suggests that the RCMIX model demonstrates satisfactory performance in predicting T-downstage by NAT for cT4 rectal cancer patients, which may provide critical insights to improve surgical strategies.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"628 ","pages":"Article 217871"},"PeriodicalIF":9.1,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144271812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of an individualized immune-related miRNA pair signature for survival prediction of neoadjuvant chemoradiotherapy in esophageal squamous cell cancer","authors":"Peng Wu ,&nbsp;Dexin Shang ,&nbsp;Li Liu ,&nbsp;Le Wang ,&nbsp;Guochao Zhang ,&nbsp;Liyan Xue ,&nbsp;Feng Li ,&nbsp;Xiaoli Zheng ,&nbsp;Yonglei Zhang ,&nbsp;Haijun Yang ,&nbsp;Yufen Yuan ,&nbsp;Ruixue Lei ,&nbsp;Dongyu Li ,&nbsp;Xuanyu Gu ,&nbsp;Ruijie Ma ,&nbsp;Jingjing Liu ,&nbsp;Jilin Peng ,&nbsp;Bohui Zhao ,&nbsp;Junhan Zhou ,&nbsp;Chuqi Lin ,&nbsp;Jie He","doi":"10.1016/j.canlet.2025.217866","DOIUrl":"10.1016/j.canlet.2025.217866","url":null,"abstract":"<div><h3>Background</h3><div>Immune-related microRNAs (ImiRNAs) have emerged as potential biomarkers owing to their universality and tissue-specificity. Although neoadjuvant chemoradiotherapy (NCRT) has been incorporated into standardized guidelines for esophageal squamous cell carcinoma (ESCC), its efficacy is hindered by tumor and individual heterogeneity. This study aimed to develop a specific ImiRNA pair signature to predict the long-term survival benefits of NCRT for ESCCs.</div></div><div><h3>Methods</h3><div>Endoscopic biopsies of 215 ESCCs were collected from three centers. ImiRNAs were identified via miRNA sequencing and immune gene annotations. A pairwise-comparison method and LASSO-Cox regression constructed prognostic models, validated in two cohorts (n = 113). Immunohistochemistry was employed to gain insights into the real tumor immune microenvironment after treatment.</div></div><div><h3>Results</h3><div>The ESCC NCRT immune-related miRNA pair signature (EN-ImiRPS), comprising six miRNA pairs, demonstrated robust prognostic accuracy for both overall survival (OS; HR: 9.76; <em>P</em> &lt; 0.001) and recurrence-free survival (RFS; HR: 5.31; <em>P</em> &lt; 0.001) in the training cohort. This performance was consistently validated in both internal and external cohorts. Furthermore, the EN-ImiRPS score outperformed pathological complete response in predicting OS and RFS. Notably, an individual miRNA expression-based model was significantly less predictive than the pair-based approach. Low-risk patients, as defined by EN-ImiRPS, exhibited significantly increased CD8⁺ T cell infiltration (<em>P</em> &lt; 0.05), indicative of enhanced anti-tumor immunity within the tumor microenvironment.</div></div><div><h3>Conclusions</h3><div>We established a multicenter, ImiRNA pair-based signature that accurately predicts long-term survival in ESCC patients receiving NCRT. The model's stability across cohorts and its association with immune microenvironment features highlight its potential for guiding personalized therapy. This study also identifies key ImiRNAs for further mechanistic exploration of tumor-immune interactions.</div></div>","PeriodicalId":9506,"journal":{"name":"Cancer letters","volume":"629 ","pages":"Article 217866"},"PeriodicalIF":9.1,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}