Pub Date : 2025-12-13DOI: 10.1016/j.seminoncol.2025.152456
Sarita Kumari , Rudrika Chandra , Abhinav Tiwari
Artificial intelligence (AI) is making remarkable strides in the field of oncology. The potential is humongous, but the perils are understated. From the perspective of gynecologic oncologists from India, we urge everyone to take a cautionary look at the rapid AI evolution in oncology.
{"title":"Artificial intelligence in gynecologic oncology: A cautionary look in the Indian context","authors":"Sarita Kumari , Rudrika Chandra , Abhinav Tiwari","doi":"10.1016/j.seminoncol.2025.152456","DOIUrl":"10.1016/j.seminoncol.2025.152456","url":null,"abstract":"<div><div>Artificial intelligence (AI) is making remarkable strides in the field of oncology. The potential is humongous, but the perils are understated. From the perspective of gynecologic oncologists from India, we urge everyone to take a cautionary look at the rapid AI evolution in oncology.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"53 2","pages":"Article 152456"},"PeriodicalIF":2.5,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145898150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-02DOI: 10.1016/j.seminoncol.2025.152454
Amr Ali Mohamed Abdelgawwad El-Sehrawy , Mohammad Y Alshahrani , Muzdalifa Mejbel Fedwi , Subbulakshmi Ganesan , Zahraa Abbas Al-Khafaji , Vimal Arora , Amrita Pal , Priya Priyadarshini Nayak , Sarvar Islomov , Chou-Yi Hsu
Melanoma, a highly aggressive type of skin cancer, has undergone incredible developments in immunotherapy, particularly in modulating T-cell immunity. T cells are essential components of the antitumor immune response and can undoubtedly influence the effectiveness of melanoma treatment. This review will evaluate the roles of the different T cell subsets (CD8+, CD4+, and Tregs) in melanoma immunity. CD8+ T cells are important effectors, as they primarily recognize and kill tumor cells. However, CD8+ T cells are often dysfunctional due to exhaustion driven by chronic antigen exposure and dysfunctional immune checkpoint pathways, specifically PD-1 and CTLA-4. On the other hand, CD4+ T cells, also known as T helper cells, play a crucial role in coordinating both pro- and antitumor immune responses. In contrast to T cells, Tregs, which are often present in the tumor microenvironment, lead to immune suppression through their activity, limiting T cell activity. This review will also examine the mechanisms of T-cell exhaustion, metabolic reprogramming within the tumor microenvironment (TME) of T-cell subsets, and the role of immune checkpoint pathways, such as CTLA-4 and PD-1, in T-cell immunity. Adoptive cell therapies (ACT), specifically Tumor-Infiltrating Lymphocyte (TIL) therapy and Chimeric Antigen Receptor (CAR) T-cell therapy, have shown the ability to rejuvenate T-cells to enhance clinical outcomes. However, several resistance mechanisms and the suppressive TME presents difficulties. Future efforts will focus on combination therapies, metabolic interventions, and novel engineering techniques to overcome barriers to T-cell function exhaustion and T-cell persistence. Evaluating biomarkers associated with early prediction for therapeutic benefit and associated toxicity is important for personalizing a particular treatment. Ultimately, this review highlights the potential of targeting T-cell exhaustion to enhance the effectiveness of T-cell-based therapies in improving outcomes for melanoma patients.
{"title":"Immuno-oncology approaches to overcome T cell exhaustion in melanoma","authors":"Amr Ali Mohamed Abdelgawwad El-Sehrawy , Mohammad Y Alshahrani , Muzdalifa Mejbel Fedwi , Subbulakshmi Ganesan , Zahraa Abbas Al-Khafaji , Vimal Arora , Amrita Pal , Priya Priyadarshini Nayak , Sarvar Islomov , Chou-Yi Hsu","doi":"10.1016/j.seminoncol.2025.152454","DOIUrl":"10.1016/j.seminoncol.2025.152454","url":null,"abstract":"<div><div>Melanoma, a highly aggressive type of skin cancer, has undergone incredible developments in immunotherapy, particularly in modulating T-cell immunity. T cells are essential components of the antitumor immune response and can undoubtedly influence the effectiveness of melanoma treatment. This review will evaluate the roles of the different T cell subsets (CD8<sup>+</sup>, CD4<sup>+</sup>, and Tregs) in melanoma immunity. CD8<sup>+</sup> T cells are important effectors, as they primarily recognize and kill tumor cells. However, CD8+ T cells are often dysfunctional due to exhaustion driven by chronic antigen exposure and dysfunctional immune checkpoint pathways, specifically PD-1 and CTLA-4. On the other hand, CD4<sup>+</sup> T cells, also known as T helper cells, play a crucial role in coordinating both pro- and antitumor immune responses. In contrast to T cells, Tregs, which are often present in the tumor microenvironment, lead to immune suppression through their activity, limiting T cell activity. This review will also examine the mechanisms of T-cell exhaustion, metabolic reprogramming within the tumor microenvironment (TME) of T-cell subsets, and the role of immune checkpoint pathways, such as CTLA-4 and PD-1, in T-cell immunity. Adoptive cell therapies (ACT), specifically Tumor-Infiltrating Lymphocyte (TIL) therapy and Chimeric Antigen Receptor (CAR) T-cell therapy, have shown the ability to rejuvenate T-cells to enhance clinical outcomes. However, several resistance mechanisms and the suppressive TME presents difficulties. Future efforts will focus on combination therapies, metabolic interventions, and novel engineering techniques to overcome barriers to T-cell function exhaustion and T-cell persistence. Evaluating biomarkers associated with early prediction for therapeutic benefit and associated toxicity is important for personalizing a particular treatment. Ultimately, this review highlights the potential of targeting T-cell exhaustion to enhance the effectiveness of T-cell-based therapies in improving outcomes for melanoma patients.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"53 1","pages":"Article 152454"},"PeriodicalIF":2.5,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145839637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oral cavity cancer remains a major clinical challenge due to its aggressive nature, rapid lymphatic spread, and limited therapeutic options. Despite advancements in diagnosis and treatment, patient prognosis continues to be poor, highlighting the urgent need for novel molecular targets. This review systematically examines the critical role of calcium (Ca²⁺) ion channels, particularly transient receptor potential (TRP) channels, in the initiation and progression of oral cancer. Comprehensive searches were conducted in Scopus, Embase, Web of Science, and Google Scholar databases up to January 2025. The focus centers on TRPA1, TRPV1-4, TRPM2, TRPM6, and TRPM8 channels, emphasizing their dysregulated expression, altered functionality, and downstream signaling in oral squamous cell carcinoma (OSCC). Emerging evidence demonstrates that aberrant TRP channel activity contributes to enhanced cell proliferation, migration, invasion, and survival, thereby promoting oral carcinogenesis. Additionally, the review explores the interplay between TRP-mediated calcium signaling and oncogenic pathways such as PI3K/AKT and MAPK, elucidating their collective impact on tumor behavior. By integrating insights from molecular biology, pharmacology, and clinical studies, this work underscores the therapeutic potential of targeting TRP channels as a novel approach in oral cancer management. Future research directions include delineating channel-protein interactions and developing selective TRP inhibitors to improve treatment outcomes.
口腔癌由于其侵袭性、快速淋巴扩散和有限的治疗选择，仍然是一个主要的临床挑战。尽管诊断和治疗取得了进步，但患者预后仍然很差，迫切需要新的分子靶点。这篇综述系统地研究了钙（Ca 2 +）离子通道，特别是瞬时受体电位（TRP）通道在口腔癌的发生和发展中的关键作用。在Scopus、Embase、Web of Science和谷歌Scholar数据库中进行了截至2025年1月的综合检索。重点关注TRPA1、TRPV1-4、TRPM2、TRPM6和TRPM8通道，强调它们在口腔鳞状细胞癌（OSCC）中的表达失调、功能改变和下游信号传导。越来越多的证据表明，异常的TRP通道活性有助于增强细胞的增殖、迁移、侵袭和存活，从而促进口腔癌的发生。此外，本综述探讨了trp介导的钙信号与PI3K/AKT和MAPK等致癌途径之间的相互作用，阐明了它们对肿瘤行为的共同影响。通过整合分子生物学、药理学和临床研究的见解，这项工作强调了靶向TRP通道作为口腔癌治疗新方法的治疗潜力。未来的研究方向包括描述通道-蛋白质相互作用和开发选择性TRP抑制剂以改善治疗效果。
{"title":"Targeting TRP channels in oral cancer: Mechanistic potential and therapeutic promise","authors":"Kaviyarasi Renu , Vishnu Priya Veeraraghavan , Harishkumar Madhyastha","doi":"10.1016/j.seminoncol.2025.152440","DOIUrl":"10.1016/j.seminoncol.2025.152440","url":null,"abstract":"<div><div>Oral cavity cancer remains a major clinical challenge due to its aggressive nature, rapid lymphatic spread, and limited therapeutic options. Despite advancements in diagnosis and treatment, patient prognosis continues to be poor, highlighting the urgent need for novel molecular targets. This review systematically examines the critical role of calcium (Ca²⁺) ion channels, particularly transient receptor potential (TRP) channels, in the initiation and progression of oral cancer. Comprehensive searches were conducted in Scopus, Embase, Web of Science, and Google Scholar databases up to January 2025. The focus centers on TRPA1, TRPV1-4, TRPM2, TRPM6, and TRPM8 channels, emphasizing their dysregulated expression, altered functionality, and downstream signaling in oral squamous cell carcinoma (OSCC). Emerging evidence demonstrates that aberrant TRP channel activity contributes to enhanced cell proliferation, migration, invasion, and survival, thereby promoting oral carcinogenesis. Additionally, the review explores the interplay between TRP-mediated calcium signaling and oncogenic pathways such as PI3K/AKT and MAPK, elucidating their collective impact on tumor behavior. By integrating insights from molecular biology, pharmacology, and clinical studies, this work underscores the therapeutic potential of targeting TRP channels as a novel approach in oral cancer management. Future research directions include delineating channel-protein interactions and developing selective TRP inhibitors to improve treatment outcomes.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"53 1","pages":"Article 152440"},"PeriodicalIF":2.5,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Artificial intelligence (AI) and nanotechnology are revolutionizing brain cancer theranostics by enhancing drug delivery and diagnostic accuracy. This review examines AI-enhanced engineering strategies for developing intelligent nanocarriers that target glioblastoma and other metastatic central nervous system malignancies. AI encompasses several computational methods, including machine learning (ML) and its subset deep learning (DL). Here, ML algorithms learn design rules for nanocarriers, and DL networks intricate pattern recognition for tumor segmentation and adaptive release. These approaches enable stimuli-responsive nanocarriers to react to tumor microenvironmental signals (eg, pH, enzyme activity) and external stimuli (eg, ultrasound), optimizing targeted medication release while minimizing off-target effects. Magnetic resonance imaging (MRI) and positron emission tomography (PET), in conjunction with AI, enhance tumor detection and segmentation, while the integration of multiomics data facilitates tailored treatment planning. Advanced technologies encompass transferrin-functionalized nanoparticles for traversing the blood-brain barrier (BBB) and dual-stimuli-responsive drug delivery systems. Notwithstanding general progress, apprehensions surrounding batch variability and industrial scalability persist. This review also addresses ethical concerns and cost disparities associated with AI-based therapeutics. The primary development target areas are federated learning for data privacy, explainable artificial intelligence (XAI) for regulatory transparency, and quantum ML for molecular-scale optimization. This paper charts the course to patient-specific, scalable neuro-oncology nanomedicine through the convergence of computational modeling, intelligent materials, and advanced imaging modalities. These themes are explored in greater detail in the introduction, where we lay the groundwork for intelligent nanocarriers, their design with the help of AI, and the clinical need for diagnostics-therapeutics convergence in brain cancer.
{"title":"Artificial intelligence-driven intelligent nanocarriers for cancer theranostics: A paradigm shift with focus on brain tumors","authors":"Mehrab Pourmadadi , Salar Mohammadi Shabestari , Hamidreza Abdouss , Abbas Rahdar , Sonia Fathi-Karkan , Sadanand Pandey","doi":"10.1016/j.seminoncol.2025.152429","DOIUrl":"10.1016/j.seminoncol.2025.152429","url":null,"abstract":"<div><div>Artificial intelligence (AI) and nanotechnology are revolutionizing brain cancer theranostics by enhancing drug delivery and diagnostic accuracy. This review examines AI-enhanced engineering strategies for developing intelligent nanocarriers that target glioblastoma and other metastatic central nervous system malignancies. AI encompasses several computational methods, including machine learning (ML) and its subset deep learning (DL). Here, ML algorithms learn design rules for nanocarriers, and DL networks intricate pattern recognition for tumor segmentation and adaptive release. These approaches enable stimuli-responsive nanocarriers to react to tumor microenvironmental signals (eg, pH, enzyme activity) and external stimuli (eg, ultrasound), optimizing targeted medication release while minimizing off-target effects. Magnetic resonance imaging (MRI) and positron emission tomography (PET), in conjunction with AI, enhance tumor detection and segmentation, while the integration of multiomics data facilitates tailored treatment planning. Advanced technologies encompass transferrin-functionalized nanoparticles for traversing the blood-brain barrier (BBB) and dual-stimuli-responsive drug delivery systems. Notwithstanding general progress, apprehensions surrounding batch variability and industrial scalability persist. This review also addresses ethical concerns and cost disparities associated with AI-based therapeutics. The primary development target areas are federated learning for data privacy, explainable artificial intelligence (XAI) for regulatory transparency, and quantum ML for molecular-scale optimization. This paper charts the course to patient-specific, scalable neuro-oncology nanomedicine through the convergence of computational modeling, intelligent materials, and advanced imaging modalities. These themes are explored in greater detail in the introduction, where we lay the groundwork for intelligent nanocarriers, their design with the help of AI, and the clinical need for diagnostics-therapeutics convergence in brain cancer.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 6","pages":"Article 152429"},"PeriodicalIF":2.5,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145496608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-08DOI: 10.1016/j.seminoncol.2025.152439
Lijun Zhang , Chengyuan Li , Jianing Zhou , Xiang Zhang , Haisheng Fang , Jingsheng Cai , Houchao Tong , Jianfei Wen , Heda Zhang , Meiping Shen , Yan Si
Papillary thyroid carcinoma (PTC) exhibits aggressive behaviors such as tumor invasion and lymph node metastasis that critically influence prognosis, yet reliable predictors of invasiveness remain elusive. This study investigated the molecular mechanisms through which ubiquitin-conjugating enzyme E2T (UBE2T) drives PTC progression. Bioinformatics analysis of TCGA/GEO datasets and validation with institutional clinical samples revealed UBE2T overexpression correlated with advanced clinicopathological features. Functional experiments demonstrated that UBE2T overexpression enhanced PTC cell invasiveness, while its knockdown suppressed malignant behaviors. Mechanistically, co-immunoprecipitation identified cytokine signaling suppressor 2 (SOCS2) as a key interactor mediating UBE2T's effects on JAK-STAT3 pathway activation. Rescue experiments and immunofluorescence confirmed UBE2T promotes oncogenesis by destabilizing SOCS2, thereby relieving its inhibition of STAT3 phosphorylation. These findings establish UBE2T as a novel regulator of PTC progression through SOCS2/JAK-STAT3 axis manipulation, providing potential therapeutic targets to mitigate metastasis and recurrence in aggressive thyroid carcinomas.
{"title":"UBE2T promotes papillary thyroid carcinoma progression by activating the JAK/STAT3 pathway via negative regulation of SOCS2","authors":"Lijun Zhang , Chengyuan Li , Jianing Zhou , Xiang Zhang , Haisheng Fang , Jingsheng Cai , Houchao Tong , Jianfei Wen , Heda Zhang , Meiping Shen , Yan Si","doi":"10.1016/j.seminoncol.2025.152439","DOIUrl":"10.1016/j.seminoncol.2025.152439","url":null,"abstract":"<div><div>Papillary thyroid carcinoma (PTC) exhibits aggressive behaviors such as tumor invasion and lymph node metastasis that critically influence prognosis, yet reliable predictors of invasiveness remain elusive. This study investigated the molecular mechanisms through which ubiquitin-conjugating enzyme E2T (UBE2T) drives PTC progression. Bioinformatics analysis of TCGA/GEO datasets and validation with institutional clinical samples revealed UBE2T overexpression correlated with advanced clinicopathological features. Functional experiments demonstrated that UBE2T overexpression enhanced PTC cell invasiveness, while its knockdown suppressed malignant behaviors. Mechanistically, co-immunoprecipitation identified cytokine signaling suppressor 2 (SOCS2) as a key interactor mediating UBE2T's effects on JAK-STAT3 pathway activation. Rescue experiments and immunofluorescence confirmed UBE2T promotes oncogenesis by destabilizing SOCS2, thereby relieving its inhibition of STAT3 phosphorylation. These findings establish UBE2T as a novel regulator of PTC progression through SOCS2/JAK-STAT3 axis manipulation, providing potential therapeutic targets to mitigate metastasis and recurrence in aggressive thyroid carcinomas.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"53 1","pages":"Article 152439"},"PeriodicalIF":2.5,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In this Perspective, we highlight colchicine, a centuries-old, widely available anti-inflammatory drug, as a promising therapeutic candidate in oncology. We synthesize evidence demonstrating its ability to target central pathways of cancer biology, including chronic inflammation, angiogenesis, cytoskeletal remodeling, and autophagy, while also mitigating treatment-related comorbidities such as cardiovascular disease.
{"title":"Colchicine as an anti-inflammatory agent improving cancer prognosis: A therapeutic repurposing perspective","authors":"Sigal Matza Porges PhD , Oded Shamriz MD, PhD , Shlomo Z Ben-Sasson PhD","doi":"10.1016/j.seminoncol.2025.152437","DOIUrl":"10.1016/j.seminoncol.2025.152437","url":null,"abstract":"<div><div>In this Perspective, we highlight colchicine, a centuries-old, widely available anti-inflammatory drug, as a promising therapeutic candidate in oncology. We synthesize evidence demonstrating its ability to target central pathways of cancer biology, including chronic inflammation, angiogenesis, cytoskeletal remodeling, and autophagy, while also mitigating treatment-related comorbidities such as cardiovascular disease.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"53 1","pages":"Article 152437"},"PeriodicalIF":2.5,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145568831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-04DOI: 10.1016/j.seminoncol.2025.152438
SuleimanIbrahim Mohammad , A.K. Kareem , Asokan Vasudevan , MM Rekha , Majid S. Jabir , PriyaPriyadarshini Nayak , Zahraa AlKhafaje , Vimal Arora , WesamR Kadhum , Kattela Chennakesavulu
The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint is a primary mechanism by which tumors evade immune surveillance, limiting the efficacy of cytotoxic T lymphocytes (CTLs) and tumor-infiltrating lymphocytes (TILs). Although immune checkpoint blockade therapies have revolutionized cancer treatment, their efficacy is restricted by acquired resistance, T-cell exhaustion, and tumor heterogeneity. The advent of CRISPR-Cas9 genome editing provides a precise and versatile approach to disrupt PD-1 or PD-L1, directly enhancing anti-tumor immune responses. Preclinical studies demonstrate that ex vivo PD-1 knockout in primary human T cells or TILs enhances proliferation, cytokine production, and cytotoxicity, resulting in improved tumor clearance in xenograft and humanized mouse models. In chimeric antigen receptor (CAR) T cell therapy, CRISPR-mediated disruption of PD-1 improves effector function, persistence, and resistance to exhaustion, with universal and allogeneic CAR-T platforms benefiting from multiplex genome editing. Direct PD-L1 knockout in tumor cells, often facilitated via nanoparticle- or biomaterial-assisted delivery, reshapes the immunosuppressive tumor microenvironment, promotes T cell infiltration, and enhances the efficacy of adoptive cellular therapy. Combination approaches integrating PD-1 editing with viral antigen targeting, long noncoding RNA (lncRNA) modulation, or conventional checkpoint blockade demonstrate synergistic anti-tumor effects. Clinically, early-phase trials in non-small cell lung cancer, mesothelin-positive solid tumors, and hematological malignancies establish the feasibility, safety, and preliminary efficacy of PD-1-deficient T cells. Despite these promising outcomes, challenges such as off-target effects, delivery efficiency, immunogenicity, long-term persistence, and regulatory considerations remain. This review aims to comprehensively evaluate preclinical and clinical studies investigating CRISPR-mediated PD-1/PD-L1 inhibition across various cancers, summarize mechanistic insights, and highlight translational opportunities and challenges for clinical implementation.
{"title":"Genome editing of immune checkpoints: CRISPR-mediated PD-1 inhibition in cancer","authors":"SuleimanIbrahim Mohammad , A.K. Kareem , Asokan Vasudevan , MM Rekha , Majid S. Jabir , PriyaPriyadarshini Nayak , Zahraa AlKhafaje , Vimal Arora , WesamR Kadhum , Kattela Chennakesavulu","doi":"10.1016/j.seminoncol.2025.152438","DOIUrl":"10.1016/j.seminoncol.2025.152438","url":null,"abstract":"<div><div>The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint is a primary mechanism by which tumors evade immune surveillance, limiting the efficacy of cytotoxic T lymphocytes (CTLs) and tumor-infiltrating lymphocytes (TILs). Although immune checkpoint blockade therapies have revolutionized cancer treatment, their efficacy is restricted by acquired resistance, T-cell exhaustion, and tumor heterogeneity. The advent of CRISPR-Cas9 genome editing provides a precise and versatile approach to disrupt PD-1 or PD-L1, directly enhancing anti-tumor immune responses. Preclinical studies demonstrate that ex vivo PD-1 knockout in primary human T cells or TILs enhances proliferation, cytokine production, and cytotoxicity, resulting in improved tumor clearance in xenograft and humanized mouse models. In chimeric antigen receptor (CAR) T cell therapy, CRISPR-mediated disruption of PD-1 improves effector function, persistence, and resistance to exhaustion, with universal and allogeneic CAR-T platforms benefiting from multiplex genome editing. Direct PD-L1 knockout in tumor cells, often facilitated via nanoparticle- or biomaterial-assisted delivery, reshapes the immunosuppressive tumor microenvironment, promotes T cell infiltration, and enhances the efficacy of adoptive cellular therapy. Combination approaches integrating PD-1 editing with viral antigen targeting, long noncoding RNA (lncRNA) modulation, or conventional checkpoint blockade demonstrate synergistic anti-tumor effects. Clinically, early-phase trials in non-small cell lung cancer, mesothelin-positive solid tumors, and hematological malignancies establish the feasibility, safety, and preliminary efficacy of PD-1-deficient T cells. Despite these promising outcomes, challenges such as off-target effects, delivery efficiency, immunogenicity, long-term persistence, and regulatory considerations remain. This review aims to comprehensively evaluate preclinical and clinical studies investigating CRISPR-mediated PD-1/PD-L1 inhibition across various cancers, summarize mechanistic insights, and highlight translational opportunities and challenges for clinical implementation.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"53 1","pages":"Article 152438"},"PeriodicalIF":2.5,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614817","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-03DOI: 10.1016/j.seminoncol.2025.152430
Shabana Sharif, Upma Sharma, Ashok Kumar Yadav
In the twenty-first century, chimeric antigen receptor (CAR)-T cell therapy has transformed cancer immunotherapy by offering novel approaches and life-saving treatments for illnesses that were previously incurable. This method is currently being used in clinical trials for solid tumors like prostate cancer and glioblastoma, as well as viral and autoimmune illnesses. It has demonstrated impressive efficacy in treating a variety of hematological malignancies. Harvesting a patient's T cells, genetically modifying them using viral vectors to express CARs that target specific antigens, and then reintroducing the altered cells into the patient is the process of CAR-T cell therapy. These CAR-T cells detect and destroy target cells specifically, regardless of the presence of the major histocompatibility complex (MHC) antigen. The major turning points in the development of CAR-T cells, from their creation to their use in medicine, are highlighted in this overview. It describes how CAR-T cells were developed historically, highlights the significant advancements that have made them a ground-breaking treatment, and talks about the obstacles that still need to be overcome, such as the high cost of production, restricted availability, and toxicity problems like cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. The review also looks at the field's future developments with the goals of increasing therapeutic uses, minimizing toxicity, and maximizing efficacy. With safer and more efficient CAR T cell therapies being developed, we are optimistic that a larger group of cancer patients may soon benefit from this innovative treatment.
{"title":"CAR-T cell therapy: A therapeutic strategy for cancer treatment","authors":"Shabana Sharif, Upma Sharma, Ashok Kumar Yadav","doi":"10.1016/j.seminoncol.2025.152430","DOIUrl":"10.1016/j.seminoncol.2025.152430","url":null,"abstract":"<div><div>In the twenty-first century, chimeric antigen receptor (CAR)-T cell therapy has transformed cancer immunotherapy by offering novel approaches and life-saving treatments for illnesses that were previously incurable. This method is currently being used in clinical trials for solid tumors like prostate cancer and glioblastoma, as well as viral and autoimmune illnesses. It has demonstrated impressive efficacy in treating a variety of hematological malignancies. Harvesting a patient's T cells, genetically modifying them using viral vectors to express CARs that target specific antigens, and then reintroducing the altered cells into the patient is the process of CAR-T cell therapy. These CAR-T cells detect and destroy target cells specifically, regardless of the presence of the major histocompatibility complex (MHC) antigen. The major turning points in the development of CAR-T cells, from their creation to their use in medicine, are highlighted in this overview. It describes how CAR-T cells were developed historically, highlights the significant advancements that have made them a ground-breaking treatment, and talks about the obstacles that still need to be overcome, such as the high cost of production, restricted availability, and toxicity problems like cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. The review also looks at the field's future developments with the goals of increasing therapeutic uses, minimizing toxicity, and maximizing efficacy. With safer and more efficient CAR T cell therapies being developed, we are optimistic that a larger group of cancer patients may soon benefit from this innovative treatment.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 6","pages":"Article 152430"},"PeriodicalIF":2.5,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145445690","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In recent years, immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of non-small cell lung cancer (NSCLC), yet treatment response and adverse events vary widely among patients. In response, the identification of reliable pretreatment biomarkers has become a major goal for many clinicians to enhance prognostication and personalized care. As such, this systematic review and meta-analysis aimed to evaluate whether pretreatment eosinophilia is associated with adverse clinical outcomes in NSCLC patients receiving ICI therapy. Following PRISMA guidelines, a comprehensive literature search was conducted across online databases through February 2025. Eligible studies included observational designs reporting associations between baseline eosinophil levels and overall survival, progression-free survival, or immune-related adverse events (irAEs) in ICI-treated NSCLC patients. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models for both unadjusted and adjusted data. Eleven studies met inclusion criteria. Pretreatment eosinophilia was associated with a nonsignificant reduction in overall survival based on both unadjusted analyses (OR: 0.79, 95% CI: 0.42–1.51 and OR: 0.74, 95% CI: 0.53–1.03, respectively). Similarly, a nonsignificant reduction in progression-free survival was found in unadjusted models (OR: 0.78, 95% CI: 0.54–1.13), whereas adjusted data revealed a significant negative association (OR: 0.68, 95% CI: 0.58–0.80). In contrast, eosinophilia was significantly associated with increased odds of irAEs in both unadjusted and adjusted analyses (OR: 3.19, 95% CI: 2.11–4.83 and OR: 3.35, 95% CI: 2.25–5.02, respectively). These findings indicate that pretreatment eosinophilia may serve as a useful prognostic biomarker indicating increased susceptibility to irAEs and potentially poorer survival outcomes in ICI-treated NSCLC patients.
{"title":"Pretreatment eosinophilia as a biomarker for adverse outcomes in non-small cell lung cancer patients receiving immune checkpoint inhibitors: A systematic review and meta-analysis","authors":"Nency Ganatra , Jacob Thompson , Rupak Desai , Jinish Doshi , Pragya Jain , Diksha Sanjana Pasnoor , Akhil Jain","doi":"10.1016/j.seminoncol.2025.152431","DOIUrl":"10.1016/j.seminoncol.2025.152431","url":null,"abstract":"<div><div>In recent years, immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of non-small cell lung cancer (NSCLC), yet treatment response and adverse events vary widely among patients. In response, the identification of reliable pretreatment biomarkers has become a major goal for many clinicians to enhance prognostication and personalized care. As such, this systematic review and meta-analysis aimed to evaluate whether pretreatment eosinophilia is associated with adverse clinical outcomes in NSCLC patients receiving ICI therapy. Following PRISMA guidelines, a comprehensive literature search was conducted across online databases through February 2025. Eligible studies included observational designs reporting associations between baseline eosinophil levels and overall survival, progression-free survival, or immune-related adverse events (irAEs) in ICI-treated NSCLC patients. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects models for both unadjusted and adjusted data. Eleven studies met inclusion criteria. Pretreatment eosinophilia was associated with a nonsignificant reduction in overall survival based on both unadjusted analyses (OR: 0.79, 95% CI: 0.42–1.51 and OR: 0.74, 95% CI: 0.53–1.03, respectively). Similarly, a nonsignificant reduction in progression-free survival was found in unadjusted models (OR: 0.78, 95% CI: 0.54–1.13), whereas adjusted data revealed a significant negative association (OR: 0.68, 95% CI: 0.58–0.80). In contrast, eosinophilia was significantly associated with increased odds of irAEs in both unadjusted and adjusted analyses (OR: 3.19, 95% CI: 2.11–4.83 and OR: 3.35, 95% CI: 2.25–5.02, respectively). These findings indicate that pretreatment eosinophilia may serve as a useful prognostic biomarker indicating increased susceptibility to irAEs and potentially poorer survival outcomes in ICI-treated NSCLC patients.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 6","pages":"Article 152431"},"PeriodicalIF":2.5,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145445725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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