Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anticancer agent capable of selectively triggering apoptosis in malignant cells while sparing normal tissues. Clinical translation of TRAIL is limited by rapid systemic clearance, poor pharmacokinetics, and intrinsic or acquired tumor resistance. Nanotechnology offers innovative solutions by stabilizing TRAIL, enhancing bioavailability, and enabling targeted delivery. Lipid-based, polymeric, and metallic nanoparticles have been engineered to improve TRAIL activity and achieve tumor-specific accumulation. TRAIL-functionalized nanocarriers also facilitate combinatorial strategies, including co-delivery with chemotherapeutics, sensitizers, or immunomodulators, to overcome resistance and potentiate apoptotic signaling. Preclinical studies in triple-negative breast cancer, glioblastoma, and colorectal carcinoma models demonstrate enhanced therapeutic efficacy, reduced systemic toxicity, and significant translational potential. This review critically examines the molecular mechanisms of TRAIL-mediated apoptosis, design principles of TRAIL-conjugated nanoparticles, and their integration into synergistic therapeutic regimens. Current limitations and future directions are discussed, emphasizing strategies to advance TRAIL nanomedicines toward clinical application. Collectively, TRAIL-functionalized nanoparticles represent a promising approach to precision oncology, bridging molecular therapeutics and nanotechnology for personalized cancer treatment.
{"title":"TRAIL-functionalized nanoparticles in cancer therapy: Molecular mechanisms and translational opportunities","authors":"Dasari Sahithi , Urushi Rehman , Ramasubbamma Ramaiah , Umme Hani , Garima Gupta , Khang Wen Goh , Prashant Kesharwani","doi":"10.1016/j.critrevonc.2026.105149","DOIUrl":"10.1016/j.critrevonc.2026.105149","url":null,"abstract":"<div><div>Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent anticancer agent capable of selectively triggering apoptosis in malignant cells while sparing normal tissues. Clinical translation of TRAIL is limited by rapid systemic clearance, poor pharmacokinetics, and intrinsic or acquired tumor resistance. Nanotechnology offers innovative solutions by stabilizing TRAIL, enhancing bioavailability, and enabling targeted delivery. Lipid-based, polymeric, and metallic nanoparticles have been engineered to improve TRAIL activity and achieve tumor-specific accumulation. TRAIL-functionalized nanocarriers also facilitate combinatorial strategies, including co-delivery with chemotherapeutics, sensitizers, or immunomodulators, to overcome resistance and potentiate apoptotic signaling. Preclinical studies in triple-negative breast cancer, glioblastoma, and colorectal carcinoma models demonstrate enhanced therapeutic efficacy, reduced systemic toxicity, and significant translational potential. This review critically examines the molecular mechanisms of TRAIL-mediated apoptosis, design principles of TRAIL-conjugated nanoparticles, and their integration into synergistic therapeutic regimens. Current limitations and future directions are discussed, emphasizing strategies to advance TRAIL nanomedicines toward clinical application. Collectively, TRAIL-functionalized nanoparticles represent a promising approach to precision oncology, bridging molecular therapeutics and nanotechnology for personalized cancer treatment.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105149"},"PeriodicalIF":5.6,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146047597","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}
Pub Date : 2026-01-22DOI: 10.1016/j.critrevonc.2026.105142
Qingze Tan , Weisong Zhang , Yihao Wang , Hao Wang , Rongqi Guo , Hao Zhu , Dongxu Ying , Yeting Li , Xia Li , Jianxiang Song
Non–small cell lung cancer (NSCLC) shows heterogeneity in benefit from immunotherapy across stages and biomarkers, underscoring the need to define tumor-microenvironment (TME) circuits that shape immune activation, spatial organization, and adaptive resistance. Beyond classical APCs, an emerging family of MHC-II⁺, RORγt-expressing APCs—including group 3 innate lymphoid cells (ILC3s), extrathymic AIRE⁺ cells (eTACs), and DC-like populations—has been reported in barrier and lymphoid tissues, shaping type-3 immunity, Th17 differentiation, tolerance, and tertiary lymphoid structure (TLS) biology. Direct phenotypic and functional characterization of bona fide RORγt⁺ APCs in human NSCLC remains limited, and many tumor-derived signals more plausibly reflect RORC-associated, type-3–skewing APC programs rather than confirmed RORγt⁺ identities. In this hypothesis-driven review, we integrate RORγt-linked APC biology, Th17 plasticity, and NSCLC immunobiology to propose a “TME signaling–RORγt-related APC programs–Th17 axis.” To prevent terminology drift, we adopt an evidence-tiered framework distinguishing bona fide RORγt⁺ APCs from inferred RORγt-associated states, and we describe functional variation using module-based descriptors (APC-program–high vs tolerogenic/TLS-linked bias). We further outline how cytokine–chemokine modules—notably CCR6–CCL20—and spatial TLS niches might couple APC programs to Th17 positioning and downstream CD8⁺ T-cell immunity, while emphasizing context-dependent bidirectionality (immune-supportive vs tumor-promoting inflammation). Finally, we highlight two regulatory modules—hypoxia–lactate/adenosine and lipid-ligand tuning of the RORγt ligand-binding domain—as plausible upstream levers that could remodel antigen presentation and type-3 outputs. Translational implications—including RORγt agonism, TME remodeling, and stage-aware biomarker hypotheses with minimally invasive profiling in malignant pleural effusion—are presented as testable hypotheses requiring validation in stage-resolved human NSCLC cohorts and mechanistic studies.
{"title":"Regulatory mechanisms and functions of RORγt⁺ antigen-presenting cells in the tumor microenvironment of non-small cell lung cancer","authors":"Qingze Tan , Weisong Zhang , Yihao Wang , Hao Wang , Rongqi Guo , Hao Zhu , Dongxu Ying , Yeting Li , Xia Li , Jianxiang Song","doi":"10.1016/j.critrevonc.2026.105142","DOIUrl":"10.1016/j.critrevonc.2026.105142","url":null,"abstract":"<div><div>Non–small cell lung cancer (NSCLC) shows heterogeneity in benefit from immunotherapy across stages and biomarkers, underscoring the need to define tumor-microenvironment (TME) circuits that shape immune activation, spatial organization, and adaptive resistance. Beyond classical APCs, an emerging family of MHC-II⁺, RORγt-expressing APCs—including group 3 innate lymphoid cells (ILC3s), extrathymic AIRE⁺ cells (eTACs), and DC-like populations—has been reported in barrier and lymphoid tissues, shaping type-3 immunity, Th17 differentiation, tolerance, and tertiary lymphoid structure (TLS) biology. Direct phenotypic and functional characterization of bona fide RORγt⁺ APCs in human NSCLC remains limited, and many tumor-derived signals more plausibly reflect RORC-associated, type-3–skewing APC programs rather than confirmed RORγt⁺ identities. In this hypothesis-driven review, we integrate RORγt-linked APC biology, Th17 plasticity, and NSCLC immunobiology to propose a “TME signaling–RORγt-related APC programs–Th17 axis.” To prevent terminology drift, we adopt an evidence-tiered framework distinguishing bona fide RORγt⁺ APCs from inferred RORγt-associated states, and we describe functional variation using module-based descriptors (APC-program–high vs tolerogenic/TLS-linked bias). We further outline how cytokine–chemokine modules—notably CCR6–CCL20—and spatial TLS niches might couple APC programs to Th17 positioning and downstream CD8⁺ T-cell immunity, while emphasizing context-dependent bidirectionality (immune-supportive vs tumor-promoting inflammation). Finally, we highlight two regulatory modules—hypoxia–lactate/adenosine and lipid-ligand tuning of the RORγt ligand-binding domain—as plausible upstream levers that could remodel antigen presentation and type-3 outputs. Translational implications—including RORγt agonism, TME remodeling, and stage-aware biomarker hypotheses with minimally invasive profiling in malignant pleural effusion—are presented as testable hypotheses requiring validation in stage-resolved human NSCLC cohorts and mechanistic studies.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105142"},"PeriodicalIF":5.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044486","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}
Pub Date : 2026-01-22DOI: 10.1016/j.critrevonc.2026.105144
Chou-Yi Hsu , Mirza R. Baig , Pareshkumar N. Patel , Gunjan Singh , Ihab M. Abdelrahim , Monthar Kadhem , Vimal Arora , Venkata Ramana Maddula , Priya Priyadarshini Nayak , Muhammad Shahid Iqbal
Glioblastoma (GBM) remains one of the most lethal human malignancies, characterized by profound heterogeneity, therapeutic resistance, and limited drug penetration across the blood–brain barrier (BBB). Irinotecan (CPT-11), a topoisomerase I inhibitor converted to its active metabolite SN-38, has emerged as a potential chemotherapeutic alternative for GBM due to its distinct mechanism of action and non–cross-resistance with temozolomide (TMZ). However, early clinical trials revealed limited efficacy, largely constrained by subtherapeutic intratumoral exposure, pharmacogenetic variability, and systemic toxicity. Recent advances have redefined the therapeutic landscape of irinotecan through three convergent strategies: biomarker-guided precision, rational combination design, and innovative drug-delivery systems.
Biomarker studies have identified predictive indicators such as TIMP-1 expression, TDP1/TOP1 activity ratio, and EGFRvIII-associated replication stress, providing a framework for patient stratification and response prediction. Mechanistic research has expanded irinotecan’s therapeutic logic beyond DNA damage, uncovering roles in p21-mediated senescence and metabolic-epigenetic modulation when combined with checkpoint inhibitors or senolytic agents. Parallel innovations in delivery ranging from liposomal and nanoparticle formulations to implantable PLGA devices, peptide–drug conjugates, and MRI-guided convection-enhanced delivery have achieved sustained intraparenchymal SN-38 exposure while minimizing systemic burden.
Collectively, these developments mark a translational shift from empirical cytotoxic therapy toward a modular, precision-engineered platform. The integration of biomarker discovery, molecularly rational combinations, and locoregional delivery systems positions irinotecan as a key component of next-generation GBM treatment paradigms, with the potential to overcome historical barriers such as BBB impermeability and therapeutic resistance.
{"title":"Innovative approaches to irinotecan-based therapies for glioblastoma: Advancements in drug delivery and combination strategies","authors":"Chou-Yi Hsu , Mirza R. Baig , Pareshkumar N. Patel , Gunjan Singh , Ihab M. Abdelrahim , Monthar Kadhem , Vimal Arora , Venkata Ramana Maddula , Priya Priyadarshini Nayak , Muhammad Shahid Iqbal","doi":"10.1016/j.critrevonc.2026.105144","DOIUrl":"10.1016/j.critrevonc.2026.105144","url":null,"abstract":"<div><div>Glioblastoma (GBM) remains one of the most lethal human malignancies, characterized by profound heterogeneity, therapeutic resistance, and limited drug penetration across the blood–brain barrier (BBB). Irinotecan (CPT-11), a topoisomerase I inhibitor converted to its active metabolite SN-38, has emerged as a potential chemotherapeutic alternative for GBM due to its distinct mechanism of action and non–cross-resistance with temozolomide (TMZ). However, early clinical trials revealed limited efficacy, largely constrained by subtherapeutic intratumoral exposure, pharmacogenetic variability, and systemic toxicity. Recent advances have redefined the therapeutic landscape of irinotecan through three convergent strategies: biomarker-guided precision, rational combination design, and innovative drug-delivery systems.</div><div>Biomarker studies have identified predictive indicators such as TIMP-1 expression, TDP1/TOP1 activity ratio, and EGFRvIII-associated replication stress, providing a framework for patient stratification and response prediction. Mechanistic research has expanded irinotecan’s therapeutic logic beyond DNA damage, uncovering roles in p21-mediated senescence and metabolic-epigenetic modulation when combined with checkpoint inhibitors or senolytic agents. Parallel innovations in delivery ranging from liposomal and nanoparticle formulations to implantable PLGA devices, peptide–drug conjugates, and MRI-guided convection-enhanced delivery have achieved sustained intraparenchymal SN-38 exposure while minimizing systemic burden.</div><div>Collectively, these developments mark a translational shift from empirical cytotoxic therapy toward a modular, precision-engineered platform. The integration of biomarker discovery, molecularly rational combinations, and locoregional delivery systems positions irinotecan as a key component of next-generation GBM treatment paradigms, with the potential to overcome historical barriers such as BBB impermeability and therapeutic resistance.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105144"},"PeriodicalIF":5.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044425","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}
Pub Date : 2026-01-22DOI: 10.1016/j.critrevonc.2026.105141
Bo Wang , Jiacheng Bi
Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that can directly kill tumor cells or coordinate other immune cells to exert antitumor effects. Transforming growth factor-β (TGF-β) is a potent inhibitory cytokine in the tumor microenvironment (TME), and its suppression of NK-cell function is an important contributor to tumor immune evasion. TGF-β can inhibit NK-cell activation and effector functions, impair NK-cell proliferation and migration, and induce the conversion of NK cells into type 1 innate lymphoid cells (ILC1s). Therefore, blocking or “hijacking” TGF-β signalling is a promising strategy to enhance the therapeutic efficacy of NK-cell-based immunotherapy. In preclinical models and, to a lesser extent, in early-phase clinical trials of TGF-β pathway inhibitors, strategies to reverse TGF-β-mediated suppression mainly include delivery of small-molecule inhibitors and recombinant protein drugs targeting TGF-β and its signalling pathways, as well as genetic engineering of NK cells. This review summarizes TGF-β signal transduction, the antitumor biological functions of NK cells, the multifaceted inhibitory effects of TGF-β on NK cells within the TME, and NK-cell-based tumor immunotherapy approaches that target TGF-β. We further highlight the limitations of current strategies and point to future directions for more precise and controllable interventions.
{"title":"TGF-β-mediated suppression of NK cell function and targeting strategies in tumor immunotherapy","authors":"Bo Wang , Jiacheng Bi","doi":"10.1016/j.critrevonc.2026.105141","DOIUrl":"10.1016/j.critrevonc.2026.105141","url":null,"abstract":"<div><div>Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that can directly kill tumor cells or coordinate other immune cells to exert antitumor effects. Transforming growth factor-β (TGF-β) is a potent inhibitory cytokine in the tumor microenvironment (TME), and its suppression of NK-cell function is an important contributor to tumor immune evasion. TGF-β can inhibit NK-cell activation and effector functions, impair NK-cell proliferation and migration, and induce the conversion of NK cells into type 1 innate lymphoid cells (ILC1s). Therefore, blocking or “hijacking” TGF-β signalling is a promising strategy to enhance the therapeutic efficacy of NK-cell-based immunotherapy. In preclinical models and, to a lesser extent, in early-phase clinical trials of TGF-β pathway inhibitors, strategies to reverse TGF-β-mediated suppression mainly include delivery of small-molecule inhibitors and recombinant protein drugs targeting TGF-β and its signalling pathways, as well as genetic engineering of NK cells. This review summarizes TGF-β signal transduction, the antitumor biological functions of NK cells, the multifaceted inhibitory effects of TGF-β on NK cells within the TME, and NK-cell-based tumor immunotherapy approaches that target TGF-β. We further highlight the limitations of current strategies and point to future directions for more precise and controllable interventions.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105141"},"PeriodicalIF":5.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146035317","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}
Pub Date : 2026-01-22DOI: 10.1016/j.critrevonc.2026.105145
Bahadır Köylü , Fatih Selçukbiricik , Sercan Aksoy , Deniz Can Güven
Head and neck squamous cell carcinoma presents a significant global health burden, with the majority of cases diagnosed at a locally advanced stage requiring multimodal therapy. While the immune checkpoint inhibitors have transformed outcomes in the recurrent/metastatic setting, their role in locally advanced head and neck squamous cell carcinoma is still evolving. In resectable disease, two recent phase III trials (KEYNOTE-689 and NIVOPOSTOP) have demonstrated meaningful improvements in event-free and disease-free survival, supporting the integration of perioperative and adjuvant immunotherapy into curative strategies. However, the data on the efficacy of immune checkpoint inhibitors in unresectable locally advanced head and neck squamous cell carcinoma remains inconsistent, underscoring the need for more precise patient selection and biomarker-driven approaches. Therapeutic strategies optimized for the timing and sequencing of immune checkpoint inhibitors in accordance with tumor microenvironment dynamics may improve clinical outcomes. Additionally, emerging immunotherapeutics, such as bispecific antibodies, oncolytic viruses, and chimeric antigen receptor T cell therapies, represents a promising frontier in the management of locally advanced head and neck squamous cell carcinoma. Considering the recent advances of the field, we aimed to synthesize current evidence and explore future directions for immunotherapy in locally advanced head and neck squamous cell carcinoma.
{"title":"Immunotherapy in locally advanced head and neck squamous cell carcinoma: The current status and future outlook","authors":"Bahadır Köylü , Fatih Selçukbiricik , Sercan Aksoy , Deniz Can Güven","doi":"10.1016/j.critrevonc.2026.105145","DOIUrl":"10.1016/j.critrevonc.2026.105145","url":null,"abstract":"<div><div>Head and neck squamous cell carcinoma presents a significant global health burden, with the majority of cases diagnosed at a locally advanced stage requiring multimodal therapy. While the immune checkpoint inhibitors have transformed outcomes in the recurrent/metastatic setting, their role in locally advanced head and neck squamous cell carcinoma is still evolving. In resectable disease, two recent phase III trials (KEYNOTE-689 and NIVOPOSTOP) have demonstrated meaningful improvements in event-free and disease-free survival, supporting the integration of perioperative and adjuvant immunotherapy into curative strategies. However, the data on the efficacy of immune checkpoint inhibitors in unresectable locally advanced head and neck squamous cell carcinoma remains inconsistent, underscoring the need for more precise patient selection and biomarker-driven approaches. Therapeutic strategies optimized for the timing and sequencing of immune checkpoint inhibitors in accordance with tumor microenvironment dynamics may improve clinical outcomes. Additionally, emerging immunotherapeutics, such as bispecific antibodies, oncolytic viruses, and chimeric antigen receptor T cell therapies, represents a promising frontier in the management of locally advanced head and neck squamous cell carcinoma. Considering the recent advances of the field, we aimed to synthesize current evidence and explore future directions for immunotherapy in locally advanced head and neck squamous cell carcinoma.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105145"},"PeriodicalIF":5.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044419","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}
Pub Date : 2026-01-22DOI: 10.1016/j.critrevonc.2026.105143
Jing Chang , Xiang Yu , Nan Xiong , Mingxuan Zhu , Changjiang Yang , Shidong Zhao , Caihong Wang , Shan Wang , Yingjiang Ye , Zhanlong Shen
Tumor microenvironment (TME) serves as a critical mediator in cancer progression and treatment response, with cancer-associated fibroblasts (CAFs) recognized as core regulators of stromal-tumor interactions. As essential components of the TME, CAFs orchestrate tumor progression and therapy resistance through multifaceted mechanisms, including extracellular matrix (ECM) remodeling, angiogenesis modulation, and immune regulation, which collectively establish a complex regulatory network. Owing to their functional heterogeneity and potent tumor-promoting properties, CAFs have emerged as promising targets for novel anti-tumor therapies. This review highlights recent advances in the understanding of CAFs, focusing on their intricate interactions within the TME and their synergistic roles in promoting therapy resistance in cancer. Furthermore, we also discuss current CAF-targeted therapeutic strategies and ongoing clinical trials, and propose future research directions to further advance this field.
{"title":"Transforming role of cancer associated fibroblasts: From therapeutic barriers to promising targets","authors":"Jing Chang , Xiang Yu , Nan Xiong , Mingxuan Zhu , Changjiang Yang , Shidong Zhao , Caihong Wang , Shan Wang , Yingjiang Ye , Zhanlong Shen","doi":"10.1016/j.critrevonc.2026.105143","DOIUrl":"10.1016/j.critrevonc.2026.105143","url":null,"abstract":"<div><div>Tumor microenvironment (TME) serves as a critical mediator in cancer progression and treatment response, with cancer-associated fibroblasts (CAFs) recognized as core regulators of stromal-tumor interactions. As essential components of the TME, CAFs orchestrate tumor progression and therapy resistance through multifaceted mechanisms, including extracellular matrix (ECM) remodeling, angiogenesis modulation, and immune regulation, which collectively establish a complex regulatory network. Owing to their functional heterogeneity and potent tumor-promoting properties, CAFs have emerged as promising targets for novel anti-tumor therapies. This review highlights recent advances in the understanding of CAFs, focusing on their intricate interactions within the TME and their synergistic roles in promoting therapy resistance in cancer. Furthermore, we also discuss current CAF-targeted therapeutic strategies and ongoing clinical trials, and propose future research directions to further advance this field.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105143"},"PeriodicalIF":5.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044442","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}
Pub Date : 2026-01-22DOI: 10.1016/j.critrevonc.2026.105146
Md Abdus Samad , Iftikhar Ahmad , Shazi Shakil , Syed Kashif Zaidi , Samina Wasi , Fahad A. Al-Abbasi , Mohammad Hassan Alhashmi , Shams Tabrez
Cancer encompasses a diverse range of disease conditions marked by the uncontrolled growth of abnormal cells and is often associated with high recurrence rates. The development and progression of cancer are closely linked to the disruption of key molecular pathways that regulate cellular and tissue homeostasis. Among the various molecular players involved, circular RNAs (circRNAs) have gained increasing attention from the scientific community because of their aberrant expression in various cancer types, leading to its progression and development. CircRNAs represent a distinct class of covalently closed RNA with distinct tissue- and cell-specific expression profiles and are essential for controlling key cellular processes. It has emerged as a crucial regulatory molecule that contributes to numerous hallmarks of cancer, such as enhanced cell proliferation, growth suppression evasion, resistance to cell death, induction of angiogenesis, invasion and metastasis, maintenance of cancer stem cells, immune evasion, metabolic reprogramming, promotion of inflammation, impairment of DNA damage, genomic instability, non-mutational epigenetic reprogramming, and therapeutic resistance. This review aims to enhance our understanding on the role of circRNAs on several cancer hallmarks and promote further research into their underlying mechanism of action, to identify and utilize them as potential therapeutic strategies.
{"title":"Circular RNAs: A key modulator of established cancer hallmarks","authors":"Md Abdus Samad , Iftikhar Ahmad , Shazi Shakil , Syed Kashif Zaidi , Samina Wasi , Fahad A. Al-Abbasi , Mohammad Hassan Alhashmi , Shams Tabrez","doi":"10.1016/j.critrevonc.2026.105146","DOIUrl":"10.1016/j.critrevonc.2026.105146","url":null,"abstract":"<div><div>Cancer encompasses a diverse range of disease conditions marked by the uncontrolled growth of abnormal cells and is often associated with high recurrence rates. The development and progression of cancer are closely linked to the disruption of key molecular pathways that regulate cellular and tissue homeostasis. Among the various molecular players involved, circular RNAs (circRNAs) have gained increasing attention from the scientific community because of their aberrant expression in various cancer types, leading to its progression and development. CircRNAs represent a distinct class of covalently closed RNA with distinct tissue- and cell-specific expression profiles and are essential for controlling key cellular processes. It has emerged as a crucial regulatory molecule that contributes to numerous hallmarks of cancer, such as enhanced cell proliferation, growth suppression evasion, resistance to cell death, induction of angiogenesis, invasion and metastasis, maintenance of cancer stem cells, immune evasion, metabolic reprogramming, promotion of inflammation, impairment of DNA damage, genomic instability, non-mutational epigenetic reprogramming, and therapeutic resistance. This review aims to enhance our understanding on the role of circRNAs on several cancer hallmarks and promote further research into their underlying mechanism of action, to identify and utilize them as potential therapeutic strategies.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105146"},"PeriodicalIF":5.6,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146044475","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}
Pub Date : 2026-01-20DOI: 10.1016/j.critrevonc.2026.105140
Chenye Xi , Ye Gao , Huishan Jiang , Yan Bian , Chuting Yu , Zheran Chen , Wei Wang , Lei Xin , Han Lin , Luowei Wang
Gastrointestinal tract cancers, including esophageal carcinoma (ESCA), gastric cancer (GC), and colorectal carcinoma (CRC), are among the most common malignant tumors with high morbidity and mortality rates, posing an increasingly significant burden on social healthcare systems. Recent evidence revealing the association between RNA modifications (collectively termed epitranscriptomics) and the tumorigenesis of gastrointestinal tract cancers has provided new insights into their pathogenesis. Among these modifications, 5-methylcytosine (m5C) is one of the most prevalent. In this narrative review, we discuss the regulators and functions of RNA m5C modification, summarize the recent studies on the roles of m5C modification in gastrointestinal tract cancer cells, briefly explore the association between RNA m5C modification and the tumor microenvironment (TME), and provide insights into its potential clinical applications as well as the remaining challenges in utilizing m5C modification for the management of gastrointestinal tract cancers. This review is based on comprehensive literature searches conducted primarily in PubMed, with no restrictions on publication date. Relevant articles were selected according to their relevance to the scope and objectives of this review. Although increasing evidence has elucidated the molecular mechanisms by which m5C RNA modification regulates the development and progression of gastrointestinal tract cancers, clinical evidence supporting its application in early screening or as a therapeutic target remains limited. Current findings are mainly derived from experimental studies and exploratory clinical studies, suggesting the gap between mechanistic insights and clinical translation.
{"title":"The novel roles of RNA 5-methylcytosine modification in gastrointestinal tract cancers","authors":"Chenye Xi , Ye Gao , Huishan Jiang , Yan Bian , Chuting Yu , Zheran Chen , Wei Wang , Lei Xin , Han Lin , Luowei Wang","doi":"10.1016/j.critrevonc.2026.105140","DOIUrl":"10.1016/j.critrevonc.2026.105140","url":null,"abstract":"<div><div>Gastrointestinal tract cancers, including esophageal carcinoma (ESCA), gastric cancer (GC), and colorectal carcinoma (CRC), are among the most common malignant tumors with high morbidity and mortality rates, posing an increasingly significant burden on social healthcare systems. Recent evidence revealing the association between RNA modifications (collectively termed epitranscriptomics) and the tumorigenesis of gastrointestinal tract cancers has provided new insights into their pathogenesis. Among these modifications, 5-methylcytosine (m5C) is one of the most prevalent. In this narrative review, we discuss the regulators and functions of RNA m5C modification, summarize the recent studies on the roles of m5C modification in gastrointestinal tract cancer cells, briefly explore the association between RNA m5C modification and the tumor microenvironment (TME), and provide insights into its potential clinical applications as well as the remaining challenges in utilizing m5C modification for the management of gastrointestinal tract cancers. This review is based on comprehensive literature searches conducted primarily in PubMed, with no restrictions on publication date. Relevant articles were selected according to their relevance to the scope and objectives of this review. Although increasing evidence has elucidated the molecular mechanisms by which m5C RNA modification regulates the development and progression of gastrointestinal tract cancers, clinical evidence supporting its application in early screening or as a therapeutic target remains limited. Current findings are mainly derived from experimental studies and exploratory clinical studies, suggesting the gap between mechanistic insights and clinical translation.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105140"},"PeriodicalIF":5.6,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032066","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}
Pub Date : 2026-01-15DOI: 10.1016/j.critrevonc.2026.105127
Ali Nakhaei , Sadaf Afshari , Elmira Mohatshami , Mohammad Jalili-Nik , Mahsa Jalali , Kasim Sakran Abass , Amir R. Afshari , Prashant Kesharwani , Amirhossein Sahebkar
Finding the proper and most effective treatment is significant because glioblastoma (GB), the most common and aggressive type of brain tumor, has been very hard for the healthcare system to deal with. Usually, standard treatments for this type of tumor take a long time to work. Even when they do, they can cause a lot of harmful side effects. One possible way to do this is to look at essential signaling pathways, especially the Wnt/beta-catenin pathway. This pathway controls some cellular connections in both healthy and unhealthy states of development. Recent findings have clarified the unique anticancer characteristics of the Wnt/beta-catenin pathway and its interrelations with other cellular pathways. These advantages have increased hopes for finding the right treatments for all types of cancer, even GB. A suggested answer focuses on critical signaling pathways, especially the Wnt/beta-catenin pathway. This pathway regulates various cellular interactions in both normal development and disease states. Recent discoveries have elucidated the distinctive anticancer properties of the Wnt/beta-catenin pathway and its interactions with other cellular pathways. These benefits have made people hopeful that they will be able to find the best treatment for all types of cancer, including GB.
{"title":"Harnessing the connection of the Wnt/beta-catenin pathway and other signaling pathways in glioblastoma multiforme","authors":"Ali Nakhaei , Sadaf Afshari , Elmira Mohatshami , Mohammad Jalili-Nik , Mahsa Jalali , Kasim Sakran Abass , Amir R. Afshari , Prashant Kesharwani , Amirhossein Sahebkar","doi":"10.1016/j.critrevonc.2026.105127","DOIUrl":"10.1016/j.critrevonc.2026.105127","url":null,"abstract":"<div><div>Finding the proper and most effective treatment is significant because glioblastoma (GB), the most common and aggressive type of brain tumor, has been very hard for the healthcare system to deal with. Usually, standard treatments for this type of tumor take a long time to work. Even when they do, they can cause a lot of harmful side effects. One possible way to do this is to look at essential signaling pathways, especially the Wnt/beta-catenin pathway. This pathway controls some cellular connections in both healthy and unhealthy states of development. Recent findings have clarified the unique anticancer characteristics of the Wnt/beta-catenin pathway and its interrelations with other cellular pathways. These advantages have increased hopes for finding the right treatments for all types of cancer, even GB. A suggested answer focuses on critical signaling pathways, especially the Wnt/beta-catenin pathway. This pathway regulates various cellular interactions in both normal development and disease states. Recent discoveries have elucidated the distinctive anticancer properties of the Wnt/beta-catenin pathway and its interactions with other cellular pathways. These benefits have made people hopeful that they will be able to find the best treatment for all types of cancer, including GB. </div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105127"},"PeriodicalIF":5.6,"publicationDate":"2026-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994677","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}
Pub Date : 2026-01-14DOI: 10.1016/j.critrevonc.2026.105128
Jiafei Ge , Lulu Gao , Lin Yu
Recent studies have increasingly highlighted the presence of microbiota within tumors and their substantial impact on tumor initiation, progression, and treatment efficacy. Intratumoral microbiota modulate tumor progression via multiple mechanisms, such as regulation of cancer cell proliferation, manipulation of immune microenvironment, and induction of the DNA damage. Notably, the distinct bacterial profiles associated with each tumor type can, in turn, promote or suppress tumor growth. Given the various mechanisms through which intratumoral microbiota influence tumor progression, a deeper understanding of their composition and functional roles in tumor dynamics is critical for the development of targeted therapies. In this review, we summarize current understanding and future perspectives of the bacterial lineages associated with different tumor types, discuss the mechanisms through which the intratumoral microbiome modulates tumor progression, and highlight emerging therapeutic strategies targeting intratumoral bacteria, including sonodynamic therapy (SDT), chemotherapy, immunotherapy, and oncolytic bacterial approaches.
{"title":"Intratumoral microbiota: Distribution, mechanisms, and therapeutic implications","authors":"Jiafei Ge , Lulu Gao , Lin Yu","doi":"10.1016/j.critrevonc.2026.105128","DOIUrl":"10.1016/j.critrevonc.2026.105128","url":null,"abstract":"<div><div>Recent studies have increasingly highlighted the presence of microbiota within tumors and their substantial impact on tumor initiation, progression, and treatment efficacy. Intratumoral microbiota modulate tumor progression via multiple mechanisms, such as regulation of cancer cell proliferation, manipulation of immune microenvironment, and induction of the DNA damage. Notably, the distinct bacterial profiles associated with each tumor type can, in turn, promote or suppress tumor growth. Given the various mechanisms through which intratumoral microbiota influence tumor progression, a deeper understanding of their composition and functional roles in tumor dynamics is critical for the development of targeted therapies. In this review, we summarize current understanding and future perspectives of the bacterial lineages associated with different tumor types, discuss the mechanisms through which the intratumoral microbiome modulates tumor progression, and highlight emerging therapeutic strategies targeting intratumoral bacteria, including sonodynamic therapy (SDT), chemotherapy, immunotherapy, and oncolytic bacterial approaches.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"219 ","pages":"Article 105128"},"PeriodicalIF":5.6,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145992324","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}
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