Critical reviews in oncology/hematology最新文献

{"title":"Pathology in motion: Automation from specimen to report","authors":"Vincenzo L’Imperio ,&nbsp;Angelo Paolo Dei Tos ,&nbsp;Maurizio Carbone ,&nbsp;Umberto Malapelle ,&nbsp;Claudio Bellevicine ,&nbsp;Giancarlo Troncone ,&nbsp;Pasquale Pisapia ,&nbsp;Stefano Marletta ,&nbsp;Matteo Brunelli ,&nbsp;Aldo Scarpa ,&nbsp;Stefano Grassi ,&nbsp;Giorgio Cazzaniga ,&nbsp;Fabio Pagni ,&nbsp;Albino Eccher","doi":"10.1016/j.critrevonc.2026.105263","DOIUrl":"10.1016/j.critrevonc.2026.105263","url":null,"abstract":"<div><div>Pathology laboratories are increasingly strained by rising diagnostic demand, greater case complexity, and limited staffing. Manual, analog workflows continue to dominate, yet they are time-consuming, prone to error, and contribute to inefficiency and staff burnout. Automation has been proposed as a strategy to address these challenges and improve sustainability. We reviewed current automation solutions available for key phases of the pathology workflow, including grossing, labeling, processing, embedding, microtomy, and archiving. Data were compared against estimates from traditional manual workflows to highlight potential gains in efficiency, accuracy, and traceability. Automation was shown to improve both efficiency and reliability across multiple stages. Advanced processing systems, such as microwave-assisted and ultrasound-based instruments, allowed faster turnaround with better tissue preservation. Embedding automation reduced operator time by more than 50%, sparing up to 40 working days annually. Automated microtomes cut sectioning times nearly in half, saving up to 470 h per year, though adoption remains limited by high cost and a slow return on investment. Automated archival systems decreased manual handling by approximately 550 h per year, while also ensuring controlled storage conditions and improved sample tracking. Automation offers clear benefits for standardization, efficiency, and diagnostic safety, while allowing staff to focus on higher-value activities. However, high implementation costs, infrastructural demands, and incomplete coverage of specialized needs remain barriers. Despite these limitations, automation represents a critical pathway toward resilient and future-ready pathology services.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"222 ","pages":"Article 105263"},"PeriodicalIF":5.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147388211","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":"Rare but distinct: A systematic review of primary neuroendocrine tumors of the breast according to WHO 2019 guidelines","authors":"Aleksandra Ciarka ,&nbsp;Karolina Skonieczna-Żydecka ,&nbsp;Marcin Folwarski ,&nbsp;Rafał Pęksa","doi":"10.1016/j.critrevonc.2026.105264","DOIUrl":"10.1016/j.critrevonc.2026.105264","url":null,"abstract":"<div><h3>Background</h3><div>Primary breast neuroendocrine tumors (BNETs) are rare malignancies recently redefined by the World Health Organization (WHO) 2019 classification, which mandates neuroendocrine morphology in over 90% of tumor cells. This systematic review aims to provide the first comprehensive analysis of BNETs strictly adhering to these diagnostic criteria.</div></div><div><h3>Methods</h3><div>A systematic search of PubMed and Embase was conducted for studies published between January 2019 and February 2025. Eligible studies included adult patients with primary BNETs diagnosed per WHO 2019 criteria, reporting clinical, pathological, or treatment data. Eight studies met inclusion criteria, encompassing 203 patients.</div></div><div><h3>Results</h3><div>BNETs predominantly affected postmenopausal women and typically presented as early-stage, hormone receptor-positive tumors. Estrogen receptor positivity was nearly universal (75.8%–100%), while HER2 overexpression was rare. Most tumors were grade 2 with low to moderate Ki-67 indices, and disease-free survival (DFS) rates were favorable (1-year DFS: 98.6%; 5-year DFS: 91.1%). Molecular studies suggested distinct genomic profiles compared to invasive breast carcinoma of no special type (IBC-NST), including lower <em>TP53</em> and <em>PIK3CA</em> mutation rates and higher frequency of <em>KMT2C</em> and <em>FOXA1</em> alterations. Somatostatin receptor 2 A (SSTR2A) expression was observed in up to 71% of cases in earlier studies, supporting potential for somatostatin analog therapy, although data were based on tumors not meeting current criteria.</div></div><div><h3>Conclusions</h3><div>BNETs represent a biologically distinct subset of breast cancers with favorable prognostic features and a consistent luminal-like phenotype. However, evidence on optimal treatment remains limited. Further large-scale, prospective studies are needed to define clinical management and validate molecular findings.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"222 ","pages":"Article 105264"},"PeriodicalIF":5.6,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147388462","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":"The role of lactic acid metabolism in anti-tumor immunity","authors":"Zhenhao Wang ,&nbsp;Hanlin Du ,&nbsp;Zhuming Yang,&nbsp;Yuanyuan Zhang,&nbsp;Zhenya Hong","doi":"10.1016/j.critrevonc.2026.105183","DOIUrl":"10.1016/j.critrevonc.2026.105183","url":null,"abstract":"<div><div>Recent studies have highlighted the pivotal role of lactate metabolism in key oncological processes, such as tumor proliferation, resistance and immune evasion. The discovery of histone lactylation pathways has further underscored the essential link between cellular energy metabolism and epigenetics, offering new insights into cancer biology. This review provides a systematic overview of lactate-immune crosstalk within the tumor microenvironment (TME), discusses the clinical relevance of lactate metabolism and lactylation biomarkers, and highlights emerging therapeutic strategies that target lactate-related pathways. By elucidating the lactate-regulated networks in cancer progression, this review offers insights into the underlying molecular mechanisms and potential pathways for the development of targeted therapies.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"221 ","pages":"Article 105183"},"PeriodicalIF":5.6,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146144887","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":"Circular RNA-mediated tumor immune escape: Mechanistic architecture and nanomedicine-enabled therapeutic reprogramming","authors":"Shenyi Jiang ,&nbsp;Yan Li ,&nbsp;Di Wu ,&nbsp;Ling Zhang ,&nbsp;Xin Tian ,&nbsp;Fandong Meng","doi":"10.1016/j.critrevonc.2026.105159","DOIUrl":"10.1016/j.critrevonc.2026.105159","url":null,"abstract":"<div><div>Circular RNAs (circRNAs) have emerged as pivotal regulators of tumor immune escape, acting through multilayered mechanisms that include miRNA sequestration, RNA-binding protein scaffolding, m⁶A-dependent stabilization, metabolic rewiring, and exosomal communication. These processes collectively sustain PD-L1 expression and stability, drive CD8⁺ T-cell exhaustion, promote Treg and MDSC expansion, skew macrophages toward immunosuppressive M2 phenotypes, and reshape glycolytic and lipid metabolic pathways to generate an immune-refractory microenvironment. In parallel, exosomal circRNAs disseminate long-range immunosuppressive signals, reinforcing therapy resistance and systemic immune dysfunction. Conversely, a newly recognized subset of “immune-activating circRNAs” induces ferroptosis, immunogenic cell death, and STING-mediated innate immune activation, highlighting the dual nature of circRNA immunoregulation. Recent advances in nanomedicine—spanning lipid nanoparticles, polymeric platforms, and biomimetic membrane-coated carriers—have enabled precise silencing of oncogenic circRNAs and efficient delivery of synthetic therapeutic circRNAs, demonstrating potent synergy with immune checkpoint inhibitors, NK-cell therapy, STING agonists, and ferroptosis inducers. Although challenges remain, including delivery specificity, biosafety, biomarker standardization, and off-target effects, the convergence of circRNA biology and advanced nanotechnology presents a transformative opportunity to develop next-generation RNA-guided cancer immunotherapies. Together, these findings position circRNAs as both key mechanistic drivers of immune escape and promising therapeutic targets for nanomedicine-enabled precision immunotherapy.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"220 ","pages":"Article 105159"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097746","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":"Neural stem cells and glioblastoma stem cells: Redefining concepts","authors":"Víctor M. Arce ,&nbsp;Lara González-Rendo ,&nbsp;Laura Porres-Ventín ,&nbsp;Valentina González-Álvarez ,&nbsp;Sabela Caamaño-Teixeira ,&nbsp;Cristina Almengló ,&nbsp;Rosa Señarís ,&nbsp;José A. Costoya","doi":"10.1016/j.critrevonc.2026.105187","DOIUrl":"10.1016/j.critrevonc.2026.105187","url":null,"abstract":"<div><div>Stem cells (SCs) represent a distinctive population of undifferentiated cells with the extraordinary ability to self-renew and differentiate into multiple cell types. Owing to this, SCs play a crucial role in maintaining tissue homeostasis, providing a source for the replacement of cell losses due to normal wear and tear. In addition, SCs display an unquestioned therapeutic potential, which has resulted in the development of several cell therapies for the treatment of different types of diseases. However, despite their remarkable potential, the therapeutic use of SCs must still face several challenges, which include ethical, legal and technical issues. Ethical and legal concerns are mainly related to the use of SCs obtained from human embryos, while technical problems mostly arise from the difficulty of appropriately directing the differentiation of the SCs to meet the tissue´s needs and the occurrence of events such as immune rejections. In addition, the safety of SC-based therapies is also under debate. Although they may offer a useful and harmless treatment for many pathologies, including some incurable and/or life-threatening diseases, a potential risk of tumorigenicity may also exist in some cases. Accumulating evidence also implicates SCs as the origin of, at least, some types of cancer. This is the case of glioblastoma (GBM), the most prevalent glioma type in adults, whose origin has been related to postnatal neural stem cells (NSCs), mainly located in the subventricular zone (SVZ) and the dentate gyrus in the hippocampus. It has been proposed that these NSCs may give rise to glioblastoma stem cells (GSCs), which through complex interactions with the tumor microenvironment exert a crucial effect on tumor growth and development.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"220 ","pages":"Article 105187"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133833","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":"Why does EGFR-targeted therapy continue to fail in breast cancer? From mechanistic deciphering to novel intervention strategies","authors":"Xiaoli An ,&nbsp;Jie Xie ,&nbsp;Weiyun Wang ,&nbsp;Ting Long ,&nbsp;Qinhao Liang ,&nbsp;Jing Hou","doi":"10.1016/j.critrevonc.2026.105186","DOIUrl":"10.1016/j.critrevonc.2026.105186","url":null,"abstract":"<div><div>Epidermal growth factor receptor (EGFR) is overexpressed in a subset of breast cancers, particularly in triple-negative breast cancer (TNBC) and endocrine-resistant patients, representing a potential therapeutic target. Although multiple EGFR inhibitors have been successfully developed and approved for non-small cell lung cancer, colorectal cancer, and other malignancies, these drugs have repeatedly failed in breast cancer treatment, with numerous clinical trials confirming their limited efficacy. The underlying cause lies in the development of drug resistance, which may arise from the activation of compensatory pathways or the abnormal stability of the EGFR protein itself, ultimately resulting in an insufficient therapeutic response. To overcome this clinical dilemma, this review discusses protein-targeted degradation technologies, such as PROTAC and LYTAC. These technologies directly induce EGFR protein degradation via the ubiquitin-proteasome or lysosomal pathways, offering a novel direction to circumvent resistance to traditional small-molecule inhibitors. Future research should focus on precision molecular subtyping to optimize patient selection, in-depth analysis of resistance mechanisms, and exploration of novel combination therapeutic strategies, thereby improving response rates, overcoming resistance challenges, and paving the way for the development of effective individualized treatment strategies for EGFR-overexpressing breast cancer.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"220 ","pages":"Article 105186"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146133804","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 pelvic lymph node dissection on oncological outcomes in patients with clinically staged non-muscle-invasive bladder cancer undergoing radical cystectomy: A systematic review","authors":"Yasmin Abu-Ghanem ,&nbsp;Jan Łaszkiewicz ,&nbsp;Ho Tin Chan ,&nbsp;Wojciech Krajewski ,&nbsp;Benjamin I. Chung ,&nbsp;Roberta Corvino ,&nbsp;Valerio Santarelli ,&nbsp;Amir Khan ,&nbsp;Felice Crocetto ,&nbsp;Youseff Ibrahim ,&nbsp;Mohamed Gad ,&nbsp;Syed Ghazi Ali Kirmani ,&nbsp;Katarina Spurna ,&nbsp;Benjamin Challacombe ,&nbsp;Rajesh Nair ,&nbsp;Elsie Mensah ,&nbsp;Ramesh Thuraraja ,&nbsp;Muhammad Shamim Khan ,&nbsp;Francesco Del Giudice","doi":"10.1016/j.critrevonc.2026.105192","DOIUrl":"10.1016/j.critrevonc.2026.105192","url":null,"abstract":"<div><h3>Introduction</h3><div>In the majority of very high-risk and selected high-risk cases of clinically non-muscle-invasive bladder cancer (NMIBC), radical cystectomy (RC) may be performed. However, the necessity of pelvic lymph node dissection (PLND) in this clinical scenario is debated. The aim of this review was to evaluate how the presence and extent of PLND influence survival outcomes.</div></div><div><h3>Materials and methods</h3><div>A systematic literature search was performed on July 6th, 2025, without language or time restrictions. Studies were considered eligible if they compared oncological outcomes between various extents of PLND during RC for NMIBC. The primary endpoint was overall survival (OS); secondary endpoints included cancer-specific survival (CSS) and recurrence-free survival (RFS).</div></div><div><h3>Results</h3><div>Nine retrospective studies comprising 20,806 patients were included. Pathological upstaging to muscle-invasive disease was observed in 19.1 %–42.0 % of patients. Seven studies evaluated OS, three CSS, and four RFS. Most studies demonstrated OS benefit associated with PLND, particularly in patients with cT1 tumors. Greater lymph node yield - especially the removal of ≥ 10 or &gt; 20 nodes - was consistently associated with improved OS. Extended PLND was linked to better CSS and RFS in several studies. However, findings for recurrence-related outcomes were heterogeneous and endpoint definitions varied.</div></div><div><h3>Conclusions</h3><div>PLND during RC for clinically NMIBC may be associated with improved survival, especially in patients with cT1 disease. Higher lymph node yield may further enhance oncologic benefit. These findings support the consideration of at least limited PLND during RC for clinically NMIBC. Prospective randomized studies are needed to establish definitive recommendations.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"220 ","pages":"Article 105192"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146144893","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":"Dextran-engineered smart nanosystems for intelligent tumor drug targeting","authors":"Muskan Jain ,&nbsp;Afsana Sheikh ,&nbsp;Taha Alqahtani ,&nbsp;Humood Al Shmrany ,&nbsp;Garima Gupta ,&nbsp;Khang Wen Goh ,&nbsp;Prashant Kesharwani","doi":"10.1016/j.critrevonc.2026.105173","DOIUrl":"10.1016/j.critrevonc.2026.105173","url":null,"abstract":"<div><div>Cancer therapy increasingly relies on nanoscale delivery systems that exploit interfacial and colloidal phenomena to enhance drug bioavailability, stability, and selectivity. Dextran-based nanocarriers have attracted considerable attention as multifunctional drug delivery platforms due to their inherent hydrophilicity, biocompatibility, and facile chemical modifiability. From a colloid and interface science perspective, dextran nanoparticles (DNPs) exhibit tunable physicochemical properties, including particle size, surface charge, and hydration shell characteristics, which critically influence their stability, biodistribution, and tumor accumulation. Recent advances in DNP engineering have enabled the development of stimuli-responsive, ligand-functionalized, and hybrid nanostructures that integrate precise control over interfacial interactions with biological systems. These smart systems facilitate targeted accumulation in the tumor microenvironment through both passive and active mechanisms, promoting enhanced cellular internalization and controlled drug release in response to pH, redox, or enzymatic stimuli. Experimental findings demonstrate that optimized DNPs improve therapeutic indices, minimize off-target toxicity, and offer a modular platform for co-delivery of chemotherapeutics and imaging agents. This review critically examines the colloidal behavior, interfacial modification strategies, and structure–function relationships of dextran-based smart nanocarriers in tumor-specific drug delivery. Emphasis is placed on the role of interfacial chemistry, supramolecular assembly, and responsive polymer architectures in mediating precise pharmacological outcomes. The discussion also highlights key challenges and emerging directions for translating dextran nanoplatforms into clinically relevant precision oncology applications.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"220 ","pages":"Article 105173"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146109109","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":"Diagnostic and prognostic significance of circulating HPV cfDNA in cervical cancer: A systematic review and meta-analysis","authors":"Preetiparna Parida ,&nbsp;Ankita Mehta ,&nbsp;Elstin Anbu Raj ,&nbsp;Shyamala Guruvare ,&nbsp;Mahadev Rao ,&nbsp;Rama Rao Damerla ,&nbsp;Shirley Lewis","doi":"10.1016/j.critrevonc.2026.105161","DOIUrl":"10.1016/j.critrevonc.2026.105161","url":null,"abstract":"<div><h3>Importance</h3><div>Human papillomavirus circulating free DNA (HPV cfDNA) is an emerging biomarker with potential utility in the detection and treatment monitoring of cervical cancer.</div></div><div><h3>Objective</h3><div>To conduct a systematic review and meta-analysis evaluating the diagnostic and prognostic performance of HPV cfDNA in cervical cancer.</div></div><div><h3>Methods</h3><div>A comprehensive literature search was conducted in PubMed, CINAHL, Cochrane Library, Scopus, and Embase through April 2025. Eligible studies reported or allowed calculation of diagnostic performance of HPV cfDNA in HPV-positive cervical cancer patients and/or included serial HPV cfDNA testing during post-treatment follow-up. Meta-analyses were conducted using a random-effects model. Heterogeneity was assessed with the I² statistic. The review followed PRISMA guidelines, and study quality was assessed using QUADAS-2.</div></div><div><h3>Results</h3><div>Of 106 studies screened, 20 met the inclusion criteria. Eleven studies contributed to the diagnostic meta-analysis and six to the prognostic analysis. The pooled sensitivity and specificity of HPV cfDNA for cervical cancer detection were 0.47 (95 % CI, 0.43–0.52) and 0.96 (95 % CI, 0.92–0.98), respectively. Positive and negative likelihood ratios were 10.49 and 0.28, with a diagnostic odds ratio of 71.31. The area under the SROC curve was 0.9825, indicating excellent overall diagnostic performance. Prognostically, HPV cfDNA positivity at 3 months post-treatment was significantly associated with reduced progression-free survival (HR = 8.50; 95 % CI, 4.69–15.41; I² = 0 %).</div></div><div><h3>Conclusions and relevance</h3><div>HPV cfDNA shows high specificity and strong prognostic value, supporting its clinical utility in cervical cancer detection and treatment surveillance.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"220 ","pages":"Article 105161"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146097766","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":"Death receptor 3: A paradoxical biomarker and therapeutic target in pan-cancer","authors":"Wenxuan Fang ,&nbsp;Junfang Du ,&nbsp;Zedong Xu ,&nbsp;Qiuyu Liu ,&nbsp;Yonghong Liu ,&nbsp;Xueni Wang","doi":"10.1016/j.critrevonc.2026.105157","DOIUrl":"10.1016/j.critrevonc.2026.105157","url":null,"abstract":"<div><div>Death receptor 3 (DR3/TNFRSF25) is a member of the tumor necrosis factor receptor superfamily, exhibiting dual roles in regulating tumor apoptosis and metastasis. Through literature review and pan-cancer analysis, this study reveals that DR3 expression exhibits distinct tumor type specificity: it is highly expressed in seven cancers, including Bladder Urothelial Carcinoma (BLCA), while showing low expression in sixteen cancers, such as Adrenocortical carcinoma (ACC). Its expression correlates with CD8⁺ T cell and natural killer (NK) cell infiltration, tumor mutational burden (TMB), and is closely associated with prognosis, exhibiting opposite trends across different cancer types. Mechanistically, DR3 activates apoptosis or programmed necrosis pathways by binding its ligand TL1A. Its interaction with NF-κB exhibits directional discrepancies across cancer types, which differentially regulate cell death. Additionally, DR3 suppresses angiogenesis and modulates antitumor immune responses. While multiple natural and synthetic compounds modulate DR3-related pathways to exert antitumor effects, no direct-targeting drugs are currently available. The presence of DR3 isoforms and decoy receptor DcR3 adds complexity to its signaling, suggesting that future clinical applications require precise evaluation considering the tumor microenvironment. In summary, DR3 is a multifunctional molecule with significant potential as a biomarker and therapeutic target. However, its duality and context-dependent effects necessitate the development of personalized strategies based on tumor molecular subtyping.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"220 ","pages":"Article 105157"},"PeriodicalIF":5.6,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146077218","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}