Pub Date : 2025-11-25DOI: 10.1016/j.critrevonc.2025.105051
Changxian Chen , Xuanzhi Wang , Tingting Yang , Xi Yuan , Na Liang , Ying Yang , Xiaorong Yang , Yixuan Pang , Yi Zhao , Chunming Li
The acidification of the tumor microenvironment is a hallmark of malignant tumors, resulting from the coordinated action of multiple pH-regulating proteins.pH-regulating Key molecules, including the sodium–hydrogen exchanger (NHE), bicarbonate transporters, monocarboxylate transporters (MCTs), V-type ATPase (V-ATPase), and carbonic anhydrases (CAs) play central roles in tumor metabolic reprogramming and microenvironmental acidification. This review re-examines the Warburg effect and proposes that cytoplasmic alkalinization is the critical switch that initiates aerobic glycolysis and inhibits oxidative phosphorylation. The review further analyzes the roles of pH-regulating proteins in tumor migration, invasion, and therapeutic resistance, and summarizes therapeutic strategies targeting these proteins. Finally, the review outlines future directions for multi-target synergistic interventions and clinical translation, thereby providing a theoretical foundation for developing novel precision therapies that target tumor pH regulation.
{"title":"The pH perspective of cancer: From warburg's misconception to therapeutic targeting of pH regulating proteins","authors":"Changxian Chen , Xuanzhi Wang , Tingting Yang , Xi Yuan , Na Liang , Ying Yang , Xiaorong Yang , Yixuan Pang , Yi Zhao , Chunming Li","doi":"10.1016/j.critrevonc.2025.105051","DOIUrl":"10.1016/j.critrevonc.2025.105051","url":null,"abstract":"<div><div>The acidification of the tumor microenvironment is a hallmark of malignant tumors, resulting from the coordinated action of multiple pH-regulating proteins.pH-regulating Key molecules, including the sodium–hydrogen exchanger (NHE), bicarbonate transporters, monocarboxylate transporters (MCTs), V-type ATPase (V-ATPase), and carbonic anhydrases (CAs) play central roles in tumor metabolic reprogramming and microenvironmental acidification. This review re-examines the Warburg effect and proposes that cytoplasmic alkalinization is the critical switch that initiates aerobic glycolysis and inhibits oxidative phosphorylation. The review further analyzes the roles of pH-regulating proteins in tumor migration, invasion, and therapeutic resistance, and summarizes therapeutic strategies targeting these proteins. Finally, the review outlines future directions for multi-target synergistic interventions and clinical translation, thereby providing a theoretical foundation for developing novel precision therapies that target tumor pH regulation.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105051"},"PeriodicalIF":5.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145615690","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 : 2025-11-23DOI: 10.1016/j.critrevonc.2025.105049
Piotr Limanówka , Aleksandra Szczuraszyk , Paulina Moszyńska , Łukasz Sędek
CD49d is a protein present on CLL cells that have been shown to be involved in pathological processes associated with this hematological malignancy. Although its prognostic significance has been shown before, new studies have emerged since. We performed a meta-analysis of studies aimed at determining the prognostic value of CD49d in CLL. We systematically searched three databases: PubMed, Web of Science, and Embase. Hazard ratios and corresponding confidence intervals for overall survival, treatment-free survival, and progression-free survival were extracted from selected studies and were pooled using random-effects models. Based on our search strategy, we retrieved a total of 562 records, with 19 being included in the final analysis, comprising 6457 patients. Results from meta-analysis showed high predictive value of CD49d in terms of OS, TFS, and PFS with estimated HR values of 2.28, 2.06, and 3.63, respectively. Heterogeneity estimation showed a lack of it in terms of OS, a low degree regarding PFS analysis, and moderate heterogeneity in terms of TFS. Our work provides evidence for the high quality of CD49d as a prognostic factor for clinical outcomes for CLL patients. It is highly suggestive that CD49d is able to distinguish patients with a higher risk of death, progression, or need for treatment without its dependence on other clinical factors, making it highly reliable in a clinical setting. It is necessary to assess its utility in the context of novel treatment options and determine the importance of bimodal expression of CD49d regarding prognostic value.
CD49d是一种存在于CLL细胞上的蛋白质，已被证明参与与这种血液恶性肿瘤相关的病理过程。虽然它的预后意义之前已经被证明，但自那以后又出现了新的研究。我们进行了一项荟萃分析，旨在确定CD49d在CLL中的预后价值。我们系统地检索了三个数据库：PubMed、Web of Science和Embase。从选定的研究中提取总生存期、无治疗生存期和无进展生存期的风险比和相应的置信区间，并使用随机效应模型进行汇总。根据我们的搜索策略，我们共检索到562条记录，其中19条被纳入最终分析，包括6457名患者。meta分析结果显示，CD49d在OS、TFS和PFS方面具有较高的预测价值，估计HR值分别为2.28、2.06和3.63。异质性估计显示，在OS方面缺乏异质性，在PFS分析方面缺乏异质性，在TFS方面具有中等异质性。我们的工作为高质量的CD49d作为CLL患者临床结果的预后因素提供了证据。这高度提示CD49d能够在不依赖其他临床因素的情况下区分死亡、进展或需要治疗风险较高的患者，使其在临床环境中具有高度可靠性。有必要评估其在新治疗方案中的效用，并确定CD49d双峰表达对预后价值的重要性。
{"title":"Prognostic value of CD49d in CLL: Systematic review and meta-analysis","authors":"Piotr Limanówka , Aleksandra Szczuraszyk , Paulina Moszyńska , Łukasz Sędek","doi":"10.1016/j.critrevonc.2025.105049","DOIUrl":"10.1016/j.critrevonc.2025.105049","url":null,"abstract":"<div><div>CD49d is a protein present on CLL cells that have been shown to be involved in pathological processes associated with this hematological malignancy. Although its prognostic significance has been shown before, new studies have emerged since. We performed a meta-analysis of studies aimed at determining the prognostic value of CD49d in CLL. We systematically searched three databases: PubMed, Web of Science, and Embase. Hazard ratios and corresponding confidence intervals for overall survival, treatment-free survival, and progression-free survival were extracted from selected studies and were pooled using random-effects models. Based on our search strategy, we retrieved a total of 562 records, with 19 being included in the final analysis, comprising 6457 patients. Results from meta-analysis showed high predictive value of CD49d in terms of OS, TFS, and PFS with estimated HR values of 2.28, 2.06, and 3.63, respectively. Heterogeneity estimation showed a lack of it in terms of OS, a low degree regarding PFS analysis, and moderate heterogeneity in terms of TFS. Our work provides evidence for the high quality of CD49d as a prognostic factor for clinical outcomes for CLL patients. It is highly suggestive that CD49d is able to distinguish patients with a higher risk of death, progression, or need for treatment without its dependence on other clinical factors, making it highly reliable in a clinical setting. It is necessary to assess its utility in the context of novel treatment options and determine the importance of bimodal expression of CD49d regarding prognostic value.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105049"},"PeriodicalIF":5.6,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145607873","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 : 2025-11-23DOI: 10.1016/j.critrevonc.2025.105050
Yiyi Zhou , Ruichen Yang , Jie Mao , Yu Huang , Yiling Lou , Shiyi Cao
Background
The prognostic significance of circulating biomarkers in appendiceal neoplasms remains inconsistent across studies, hindering their clinical implementation for prognostic stratification. This meta-analysis aims to estimate and compare the prognostic value of various circulating biomarkers in appendiceal neoplasms.
Materials and methods
We conducted a systematic literature search across PubMed, Web of Science, Cochrane Library, OVID platforms (Embase/MEDLINE) and Scopus from database inception to February 23, 2025, to identify studies investigating associations between circulating biomarkers and survival outcomes. Only retrospective cohorts are included. Hazard ratios (HRs) derived from Cox regression analyses were pooled using random-effects models. Newcastle-Ottawa Scale (NOS) was used to assess the quality of the studies. We performed pairwise and Bayesian network meta-analysis to establish prognostic hierarchy among biomarkers.
Results
19 studies comprising 8478 patients evaluating six circulating biomarkers (CA125, CA19–9, CEA, Neutrophil-to-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR), and circulating tumor DNA (ctDNA)) were included. CA125 demonstrated independent prognostic value for both OS (HR=2.46[1.78–3.38, 95 % CI]) and DFS/PFS (HR=1.72[1.14–2.59, 95 % CI]), while CA19–9 specifically predicted DFS/PFS deterioration (HR=2.69[2.01–3.61, 95 % CI]). CEA elevation was independently associated with poorer OS (HR=2.04[1.45–2.88, 95 % CI]). ctDNA detection also showed prognostic value for adverse outcomes. Elevated NLR and PLR levels showed no significant associations with survival outcomes. Bayesian network analysis revealed no significant differences.
Conclusions
Preoperative elevation of serum CA125, CA19–9, and CEA levels demonstrates significant prognostic value in appendiceal neoplasms. While ctDNA retains prognostic significance, inflammatory markers NLR and PLR show limited clinical utility.
{"title":"The relationship between circulating tumor biomarkers and prognosis of appendix cancer: A systematic review and meta-analysis","authors":"Yiyi Zhou , Ruichen Yang , Jie Mao , Yu Huang , Yiling Lou , Shiyi Cao","doi":"10.1016/j.critrevonc.2025.105050","DOIUrl":"10.1016/j.critrevonc.2025.105050","url":null,"abstract":"<div><h3>Background</h3><div>The prognostic significance of circulating biomarkers in appendiceal neoplasms remains inconsistent across studies, hindering their clinical implementation for prognostic stratification. This meta-analysis aims to estimate and compare the prognostic value of various circulating biomarkers in appendiceal neoplasms.</div></div><div><h3>Materials and methods</h3><div>We conducted a systematic literature search across PubMed, Web of Science, Cochrane Library, OVID platforms (Embase/MEDLINE) and Scopus from database inception to February 23, 2025, to identify studies investigating associations between circulating biomarkers and survival outcomes. Only retrospective cohorts are included. Hazard ratios (HRs) derived from Cox regression analyses were pooled using random-effects models. Newcastle-Ottawa Scale (NOS) was used to assess the quality of the studies. We performed pairwise and Bayesian network meta-analysis to establish prognostic hierarchy among biomarkers.</div></div><div><h3>Results</h3><div>19 studies comprising 8478 patients evaluating six circulating biomarkers (CA125, CA19–9, CEA, Neutrophil-to-lymphocyte ratio (NLR), Platelet-to-lymphocyte ratio (PLR), and circulating tumor DNA (ctDNA)) were included. CA125 demonstrated independent prognostic value for both OS (HR=2.46[1.78–3.38, 95 % CI]) and DFS/PFS (HR=1.72[1.14–2.59, 95 % CI]), while CA19–9 specifically predicted DFS/PFS deterioration (HR=2.69[2.01–3.61, 95 % CI]). CEA elevation was independently associated with poorer OS (HR=2.04[1.45–2.88, 95 % CI]). ctDNA detection also showed prognostic value for adverse outcomes. Elevated NLR and PLR levels showed no significant associations with survival outcomes. Bayesian network analysis revealed no significant differences.</div></div><div><h3>Conclusions</h3><div>Preoperative elevation of serum CA125, CA19–9, and CEA levels demonstrates significant prognostic value in appendiceal neoplasms. While ctDNA retains prognostic significance, inflammatory markers NLR and PLR show limited clinical utility.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105050"},"PeriodicalIF":5.6,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145607876","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 : 2025-11-22DOI: 10.1016/j.critrevonc.2025.105048
Chih-Chen Tzang , Hui-Wen Wu , Chiao-An Luo , Ewen Shengyao Huang , Wei-Chen Lin , Yan-Hua Chen , Zi-Yi Chang , Yi-Ting Lee , Yuan-Fu Kang , Bor-Show Tzang , Tsai-Ching Hsu
Background
Breast cancer is a leading cause of cancer-related mortality in women worldwide. Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown efficacy in improving progression-free survival (PFS), particularly in patients with breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutations and homologous recombination deficiency (HRD).
Methods
This umbrella review of systematic reviews and meta-analyses assessed the effectiveness and safety of PARP inhibitors (PARPi) across various breast cancer subtypes.
Results
PARPi significantly improved PFS and overall response rate (ORR), especially in BRCA-mutated and triple-negative breast cancer (TNBC) populations. However, overall survival (OS) benefits were modest and often not statistically significant. PARPi treatment was associated with increased risks of anemia, neutropenia, and gastrointestinal toxicities, although the rates of overall Grade ≥ 3 adverse events were comparable to those of chemotherapy.
Conclusions
This review highlights the clinical value of PARP inhibitors (PARPi), particularly in genetically defined subgroups, and underscores the need for biomarker-driven treatment strategies and further exploration of combination regimens.
{"title":"Effectiveness and safety of PARP inhibitors in breast cancer: An umbrella review of systematic reviews and meta-analyses","authors":"Chih-Chen Tzang , Hui-Wen Wu , Chiao-An Luo , Ewen Shengyao Huang , Wei-Chen Lin , Yan-Hua Chen , Zi-Yi Chang , Yi-Ting Lee , Yuan-Fu Kang , Bor-Show Tzang , Tsai-Ching Hsu","doi":"10.1016/j.critrevonc.2025.105048","DOIUrl":"10.1016/j.critrevonc.2025.105048","url":null,"abstract":"<div><h3>Background</h3><div>Breast cancer is a leading cause of cancer-related mortality in women worldwide. Poly(ADP-ribose) polymerase inhibitors (PARPi) have shown efficacy in improving progression-free survival (PFS), particularly in patients with breast cancer susceptibility genes 1 and 2 (BRCA1/2) mutations and homologous recombination deficiency (HRD).</div></div><div><h3>Methods</h3><div>This umbrella review of systematic reviews and meta-analyses assessed the effectiveness and safety of PARP inhibitors (PARPi) across various breast cancer subtypes.</div></div><div><h3>Results</h3><div>PARPi significantly improved PFS and overall response rate (ORR), especially in BRCA-mutated and triple-negative breast cancer (TNBC) populations. However, overall survival (OS) benefits were modest and often not statistically significant. PARPi treatment was associated with increased risks of anemia, neutropenia, and gastrointestinal toxicities, although the rates of overall Grade ≥ 3 adverse events were comparable to those of chemotherapy.</div></div><div><h3>Conclusions</h3><div>This review highlights the clinical value of PARP inhibitors (PARPi), particularly in genetically defined subgroups, and underscores the need for biomarker-driven treatment strategies and further exploration of combination regimens.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105048"},"PeriodicalIF":5.6,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598325","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 : 2025-11-22DOI: 10.1016/j.critrevonc.2025.105044
Sile Li , Yuanxin Li , Man Yan Hui , Asif Rashid , Hong Kee Tan , Shing Chan , Wilson Yau Ki Chan , Kee See Lam , Wenwei Tu , Wing Leung
Chimeric antigen receptor (CAR) T-cell therapy utilizes synthetic biology techniques to engineer T cells to specifically target tumor cells using most commonly single-chain variable fragments (scFvs) to recognize tumor-associated antigens, which has been successfully applied to patients with B-lineage hematologic malignancies including leukemia, lymphoma and multiple myeloma. However, treatment outcomes for relapsed or refractory (R/R) T-cell malignancies remain suboptimal. A significant challenge is the shared antigens between malignant and normal T cells, leading to fratricide among CAR T cells. Moreover, the presence of malignant T cells in patients’ leukapheresis may increase risk of relapse. Post-infusion, patients may experience severe T-cell aplasia, rendering the cancer patients who are generally immunocompromised even more immunodeficient. This review article explores CAR-based cellular therapy, including immune effector cells (IECs) such as conventional T cell subsets, natural killer (NK) cells, natural killer T (NKT) cells, cytokine-induced killer (CIK) cells, and γδ T cells for T-cell malignancies. We discuss multiple antigen-targeting, emerging technologies, and the latest clinical trials in attempt to improve CAR-based therapy for T-lineage neoplasms.
{"title":"Chimeric antigen receptor-based cellular therapy for T-cell malignancies","authors":"Sile Li , Yuanxin Li , Man Yan Hui , Asif Rashid , Hong Kee Tan , Shing Chan , Wilson Yau Ki Chan , Kee See Lam , Wenwei Tu , Wing Leung","doi":"10.1016/j.critrevonc.2025.105044","DOIUrl":"10.1016/j.critrevonc.2025.105044","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T-cell therapy utilizes synthetic biology techniques to engineer T cells to specifically target tumor cells using most commonly single-chain variable fragments (scFvs) to recognize tumor-associated antigens, which has been successfully applied to patients with B-lineage hematologic malignancies including leukemia, lymphoma and multiple myeloma. However, treatment outcomes for relapsed or refractory (R/R) T-cell malignancies remain suboptimal. A significant challenge is the shared antigens between malignant and normal T cells, leading to fratricide among CAR T cells. Moreover, the presence of malignant T cells in patients’ leukapheresis may increase risk of relapse. Post-infusion, patients may experience severe T-cell aplasia, rendering the cancer patients who are generally immunocompromised even more immunodeficient. This review article explores CAR-based cellular therapy, including immune effector cells (IECs) such as conventional T cell subsets, natural killer (NK) cells, natural killer T (NKT) cells, cytokine-induced killer (CIK) cells, and γδ T cells for T-cell malignancies. We discuss multiple antigen-targeting, emerging technologies, and the latest clinical trials in attempt to improve CAR-based therapy for T-lineage neoplasms.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105044"},"PeriodicalIF":5.6,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598189","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 : 2025-11-21DOI: 10.1016/j.critrevonc.2025.105045
Andrea Visentin , Alessandro Cellini , Francesco Angotzi , Sara Pepe , Francesca Romana Mauro
The combination of ibrutinib and venetoclax (I+V), has shown benefit in treating chronic lymphocytic leukemia (CLL) due to their complementary mechanisms of action and synergistic effects. The fixed duration of the I+V regimen results in high response rates, including undetectable measurable residual disease (MRD), in treatment-naïve patients with CLL, even among those with high-risk abnormalities. Additionally, the efficacy of the I+V combination is being currently evaluated in an MRD-guided approach, where treatment continues until a deep response with undetectable MRD (uMRD) is achieved. This review analyzes data from 7 clinical trials that investigated the efficacy and safety of the I+V regimen when administered as a first-line treatment in at least 50 patients, either in a fixed-duration schedule (CAPTIVATE and GLOW trials) or in an MRD-guided manner (MDACC, FLAIR, ERADIC, and HOVON NEXT STEP trials). Despite variations in patient characteristics, treatment protocols, follow-up durations, and treatment lengths, the I+V combination led to high response rates (% range, 81–97) and undetectable MRD (% range, 52–82) with high progression-free survival (PFS) rates. The MRD-guided treatment yields promising results, with high rates of deep responses and prolonged PFS, even in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) genes (3-year PFS: 90 % in the MDACC trial and 98 % in the FLAIR trial) and in those with TP53 disruptions (3-year PFS: 86.1 % in the MDACC trial). The I+V regimen is generally manageable and well-tolerated, with toxicities consistent with those reported for single-agent use. Nonetheless, concerns regarding cardiovascular toxicities have been raised, particularly among older patients.
伊鲁替尼和venetoclax （I+V）联合治疗慢性淋巴细胞白血病（CLL）由于其互补的作用机制和协同效应而显示出益处。I+V方案的固定持续时间导致高应答率，包括无法检测到的可测量的残留疾病（MRD），在treatment-naïve CLL患者中，即使在高危异常患者中也是如此。此外，目前正在以MRD指导的方法评估I+V联合治疗的疗效，该方法持续治疗，直到达到无法检测到的MRD （uMRD）的深度反应。本综述分析了来自7项临床试验的数据，这些试验调查了I+V方案作为一线治疗在至少50例患者中的有效性和安全性，无论是在固定时间计划（CAPTIVATE和GLOW试验）还是在mrd指导下（MDACC， FLAIR， ERADIC和HOVON NEXT STEP试验）。尽管患者特征、治疗方案、随访时间和治疗时间存在差异，但I+V联合治疗导致高缓解率（%范围，81-97）和不可检测的MRD（%范围，52-82）和高无进展生存率（PFS）。mrd引导的治疗产生了令人鼓舞的结果，具有高的深度应答率和延长的PFS，即使在具有未突变的免疫球蛋白重链可变区（IGHV）基因的患者中（3年PFS: MDACC试验中的90%和FLAIR试验中的98%）和TP53破坏的患者中（3年PFS: MDACC试验中的86.1%）。I+V方案通常是可控且耐受性良好的，其毒性与单药使用报告的毒性一致。尽管如此，对心血管毒性的担忧已经增加，特别是在老年患者中。
{"title":"Venetoclax and ibrutinib: Two partners for the front-line treatment of chronic lymphocytic leukemia","authors":"Andrea Visentin , Alessandro Cellini , Francesco Angotzi , Sara Pepe , Francesca Romana Mauro","doi":"10.1016/j.critrevonc.2025.105045","DOIUrl":"10.1016/j.critrevonc.2025.105045","url":null,"abstract":"<div><div>The combination of ibrutinib and venetoclax (I+V), has shown benefit in treating chronic lymphocytic leukemia (CLL) due to their complementary mechanisms of action and synergistic effects. The fixed duration of the I+V regimen results in high response rates, including undetectable measurable residual disease (MRD), in treatment-naïve patients with CLL, even among those with high-risk abnormalities. Additionally, the efficacy of the I+V combination is being currently evaluated in an MRD-guided approach, where treatment continues until a deep response with undetectable MRD (uMRD) is achieved. This review analyzes data from 7 clinical trials that investigated the efficacy and safety of the I+V regimen when administered as a first-line treatment in at least 50 patients, either in a fixed-duration schedule (CAPTIVATE and GLOW trials) or in an MRD-guided manner (MDACC, FLAIR, ERADIC, and HOVON NEXT STEP trials). Despite variations in patient characteristics, treatment protocols, follow-up durations, and treatment lengths, the I+V combination led to high response rates (% range, 81–97) and undetectable MRD (% range, 52–82) with high progression-free survival (PFS) rates. The MRD-guided treatment yields promising results, with high rates of deep responses and prolonged PFS, even in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) genes (3-year PFS: 90 % in the MDACC trial and 98 % in the FLAIR trial) and in those with TP53 disruptions (3-year PFS: 86.1 % in the MDACC trial). The I+V regimen is generally manageable and well-tolerated, with toxicities consistent with those reported for single-agent use. Nonetheless, concerns regarding cardiovascular toxicities have been raised, particularly among older patients.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105045"},"PeriodicalIF":5.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145590264","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 : 2025-11-21DOI: 10.1016/j.critrevonc.2025.105043
Yuhao Zhao , Yuqi Liu , Yinzhou Xu , Zixuan Guo , Xiyue Zhang , Zipeng Ma
Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, with genetic alterations playing critical roles in tumor development and patient outcomes. Among the genetic alterations, mutations in the MSH2 gene, a key component of the DNA mismatch repair system, garner significant attention for their influence on CRC pathogenesis and prognosis. This review synthesizes current research centered on whole genome sequencing (WGS) technologies that enable comprehensive characterization of MSH2 mutations and their molecular underpinnings. We examine the spectrum of MSH2 mutation types identified by WGS, their impact on tumor microenvironment modulation, therapeutic response variability, and patient survival rates. Despite advances, challenges remain in fully elucidating the prognostic value of MSH2 mutations because tumor heterogeneity leads to variable mutation expression across tumor cells, and complex gene-environment interactions influence how these mutations affect disease progression and treatment outcomes. By integrating multiple WGS datasets from different cohorts, this review first highlights the role of data integration in enhancing the robustness of findings. It then discusses the potential of MSH2 mutations as robust prognostic biomarkers and their emerging role in guiding personalized treatment strategies for CRC. Based on this synthesis, we propose a novel clinical decision-making framework that leverages MSH2 status to stratify patients, optimize immunotherapy selection, and enable dynamic monitoring through circulating tumor DNA (ctDNA) profiling. This framework represents a practical tool for translating genomic insights into precision oncology practice. These findings, including the characterization of MSH2 mutation types, their biological impacts, and clinical applications, underscore the promise of leveraging genomic insights to enhance precision oncology approaches and improve clinical outcomes for CRC patients.
{"title":"MSH2 in colorectal cancer: A comprehensive review of molecular mechanisms, clinical prognosis, and a precision oncology framework","authors":"Yuhao Zhao , Yuqi Liu , Yinzhou Xu , Zixuan Guo , Xiyue Zhang , Zipeng Ma","doi":"10.1016/j.critrevonc.2025.105043","DOIUrl":"10.1016/j.critrevonc.2025.105043","url":null,"abstract":"<div><div>Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, with genetic alterations playing critical roles in tumor development and patient outcomes. Among the genetic alterations, mutations in the MSH2 gene, a key component of the DNA mismatch repair system, garner significant attention for their influence on CRC pathogenesis and prognosis. This review synthesizes current research centered on whole genome sequencing (WGS) technologies that enable comprehensive characterization of MSH2 mutations and their molecular underpinnings. We examine the spectrum of MSH2 mutation types identified by WGS, their impact on tumor microenvironment modulation, therapeutic response variability, and patient survival rates. Despite advances, challenges remain in fully elucidating the prognostic value of MSH2 mutations because tumor heterogeneity leads to variable mutation expression across tumor cells, and complex gene-environment interactions influence how these mutations affect disease progression and treatment outcomes. By integrating multiple WGS datasets from different cohorts, this review first highlights the role of data integration in enhancing the robustness of findings. It then discusses the potential of MSH2 mutations as robust prognostic biomarkers and their emerging role in guiding personalized treatment strategies for CRC. Based on this synthesis, we propose a novel clinical decision-making framework that leverages MSH2 status to stratify patients, optimize immunotherapy selection, and enable dynamic monitoring through circulating tumor DNA (ctDNA) profiling. This framework represents a practical tool for translating genomic insights into precision oncology practice. These findings, including the characterization of MSH2 mutation types, their biological impacts, and clinical applications, underscore the promise of leveraging genomic insights to enhance precision oncology approaches and improve clinical outcomes for CRC patients.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105043"},"PeriodicalIF":5.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145590197","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 : 2025-11-20DOI: 10.1016/j.critrevonc.2025.105037
Onyekachi J. Okpasuo , Olamide T. Olaoba , Patrick Bokolo , Aloysius S. Aleke , Ayobami Dare , Temitope I. Adelusi , Christa D. Jackson
The landscape of antibody-based cancer therapies has evolved dramatically since the first monoclonal antibody (mAb) was approved for cancer treatment three decades ago. Advances in recombinant DNA and molecular engineering have transformed monospecific mAbs into multi-specific and multi-modal constructs, revolutionizing oncology. Unlike traditional mAbs, next-generation antibodies, including bispecific antibodies, antibody-drug conjugates (ADCs), and radionuclide-antibody conjugates (RACs), enable synergistic targeting of tumor-associated antigens (TAAs), immunomodulatory receptors, and immune cell engagement while delivering cytotoxic payloads. These constructs enhance specificity, tumor penetration, and therapeutic efficacy while minimizing off-target toxicity. Multi-specific antibodies, designed to bind multiple antigens or distinct epitopes, leverage structural innovations like IgG-like formats for stability and non-IgG-like formats for rapid clearance and improved tissue penetration. ADCs and RACs deliver potent chemotherapeutic or radiotherapeutic agents directly to tumor cells, offering dual therapeutic-diagnostic potential and reducing systemic toxicity compared to conventional treatments. This review explores the structural diversity, mechanisms of action, therapeutic targets, and clinical applications of these advanced antibody formats across different cancer indications. It highlights how multi-modal approaches overcome resistance and enhance synergy with immunotherapies targeting both innate and adaptive immune cells and molecules, aligning with personalized medicine paradigms. By integrating cutting-edge molecular engineering with clinical insights, this review highlights the transformative potential of antibody-based therapies in reshaping cancer treatment and improving patient outcomes.
{"title":"The evolving landscape of antibody-based cancer therapies: From monospecific to multi-specific and beyond","authors":"Onyekachi J. Okpasuo , Olamide T. Olaoba , Patrick Bokolo , Aloysius S. Aleke , Ayobami Dare , Temitope I. Adelusi , Christa D. Jackson","doi":"10.1016/j.critrevonc.2025.105037","DOIUrl":"10.1016/j.critrevonc.2025.105037","url":null,"abstract":"<div><div>The landscape of antibody-based cancer therapies has evolved dramatically since the first monoclonal antibody (mAb) was approved for cancer treatment three decades ago. Advances in recombinant DNA and molecular engineering have transformed monospecific mAbs into multi-specific and multi-modal constructs, revolutionizing oncology. Unlike traditional mAbs, next-generation antibodies, including bispecific antibodies, antibody-drug conjugates (ADCs), and radionuclide-antibody conjugates (RACs), enable synergistic targeting of tumor-associated antigens (TAAs), immunomodulatory receptors, and immune cell engagement while delivering cytotoxic payloads. These constructs enhance specificity, tumor penetration, and therapeutic efficacy while minimizing off-target toxicity. Multi-specific antibodies, designed to bind multiple antigens or distinct epitopes, leverage structural innovations like IgG-like formats for stability and non-IgG-like formats for rapid clearance and improved tissue penetration. ADCs and RACs deliver potent chemotherapeutic or radiotherapeutic agents directly to tumor cells, offering dual therapeutic-diagnostic potential and reducing systemic toxicity compared to conventional treatments. This review explores the structural diversity, mechanisms of action, therapeutic targets, and clinical applications of these advanced antibody formats across different cancer indications. It highlights how multi-modal approaches overcome resistance and enhance synergy with immunotherapies targeting both innate and adaptive immune cells and molecules, aligning with personalized medicine paradigms. By integrating cutting-edge molecular engineering with clinical insights, this review highlights the transformative potential of antibody-based therapies in reshaping cancer treatment and improving patient outcomes.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105037"},"PeriodicalIF":5.6,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582790","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 : 2025-11-20DOI: 10.1016/j.critrevonc.2025.105035
Jacopo Canzian , Flavia Jacobs , Anna Floreani , Chiara Miggiano , Paola Tiberio , Chiara Pozzi , Armando Santoro , Alberto Zambelli , Maria Rescigno , Rita De Sanctis
The intratumoral microbiome has recently emerged as a critical component of the tumor microenvironment in breast cancer (BC). BC exhibits a uniquely rich and diverse microbial community, characterized by phyla such as Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. In addition, distinct microbial signatures were observed in different molecular subtypes, with hormone receptor-positive BC showing the highest microbial diversity and the most robust microbiome. These microbial constituents interact with neoplastic and immune cells, influencing estrogen metabolism, DNA damage, epithelial-to-mesenchymal transition (EMT), inflammation, and response to anticancer therapy. For instance, Fusobacterium nucleatum is among the main microbial components implicated in BC, contributing to carcinogenesis, tumor growth, and metastasis through mechanisms involving DNA damage (e.g., activating the E-cadherin/β-catenin signaling pathway), EMT (e.g., inducing the expression of EMT markers, including cadherins and vimentin), and immunoregulatory effects (e.g., regulating IL-1β expression and activating the TLR4/NF-κB signaling pathway). It has also been shown to induce chemoresistance by enhancing cancer cell stemness and viability, whereas its elimination improves sensitivity to anticancer therapies and immunotherapy. Besides investigating the specific activity of microbial components, recent studies have focused on the intratumoral microbiome prognostic role. Methodological variability remains a significant barrier to standardization and cross-study comparisons. Nevertheless, subtype-specific microbial signatures have demonstrated prognostic and predictive value, correlating with stage, treatment response, and immune cell infiltration. Understanding the interplay between the intratumoral microbiome, host genetics, and treatment response may ultimately inform the development of microbiome-based biomarkers and therapeutic strategies, positioning the tumor microbiota as a potential modifiable target in personalized BC care.
{"title":"Intratumoral microbiome in breast cancer: A hidden player in tumor development, progression and treatment response","authors":"Jacopo Canzian , Flavia Jacobs , Anna Floreani , Chiara Miggiano , Paola Tiberio , Chiara Pozzi , Armando Santoro , Alberto Zambelli , Maria Rescigno , Rita De Sanctis","doi":"10.1016/j.critrevonc.2025.105035","DOIUrl":"10.1016/j.critrevonc.2025.105035","url":null,"abstract":"<div><div>The intratumoral microbiome has recently emerged as a critical component of the tumor microenvironment in breast cancer (BC). BC exhibits a uniquely rich and diverse microbial community, characterized by phyla such as Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. In addition, distinct microbial signatures were observed in different molecular subtypes, with hormone receptor-positive BC showing the highest microbial diversity and the most robust microbiome. These microbial constituents interact with neoplastic and immune cells, influencing estrogen metabolism, DNA damage, epithelial-to-mesenchymal transition (EMT), inflammation, and response to anticancer therapy. For instance, <em>Fusobacterium nucleatum</em> is among the main microbial components implicated in BC, contributing to carcinogenesis, tumor growth, and metastasis through mechanisms involving DNA damage (e.g., activating the E-cadherin/β-catenin signaling pathway), EMT (e.g., inducing the expression of EMT markers, including cadherins and vimentin), and immunoregulatory effects (e.g., regulating IL-1β expression and activating the TLR4/NF-κB signaling pathway). It has also been shown to induce chemoresistance by enhancing cancer cell stemness and viability, whereas its elimination improves sensitivity to anticancer therapies and immunotherapy. Besides investigating the specific activity of microbial components, recent studies have focused on the intratumoral microbiome prognostic role. Methodological variability remains a significant barrier to standardization and cross-study comparisons. Nevertheless, subtype-specific microbial signatures have demonstrated prognostic and predictive value, correlating with stage, treatment response, and immune cell infiltration. Understanding the interplay between the intratumoral microbiome, host genetics, and treatment response may ultimately inform the development of microbiome-based biomarkers and therapeutic strategies, positioning the tumor microbiota as a potential modifiable target in personalized BC care.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105035"},"PeriodicalIF":5.6,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582834","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 : 2025-11-20DOI: 10.1016/j.critrevonc.2025.105039
Joecelyn Kirani Tan , Sri Vidya Niharika Gullapalli , Pratima Chapagain , Aruni Ghose , Armand Grollemund , Alex Speechley , Maryam Hasanova , Sayali D. Shinde , Advaith Kandala , Akash Maniam , Ankit Jain , Sola Adeleke , Sara Elena Rebuzzi , Jeremy Yuen-Chun Teoh , Yüksel Ürün , Giuseppe Luigi Banna , Stergios Boussios
Urological cancers, including prostate, bladder, renal, and testicular cancers, present significant challenges in terms of incidence, mortality, and treatment resistance. Immunotherapy, particularly bispecific T-cell engagers (BiTEs), has emerged as a promising therapeutic strategy, targeting tumor-specific antigens to activate T cells and enhance anti-tumor immunity. BiTEs, such as pasotuxizumab for prostate cancer, and CD3 ×B7-H3 BiTE for bladder cancer, demonstrate potential in overcoming the limitations of traditional therapies and immune checkpoint inhibitors. This review explores the application of BiTEs in urological cancers, highlighting their clinical outcomes, challenges, and future prospects. Although BiTEs offer significant advantages, including selective T-cell activation and low-dose efficacy, obstacles such as on-target off-tumor toxicity, the immunosuppressive tumour microenvironment (TME), and immune-related adverse effects need to be addressed for broader clinical success. Combination therapies with immune checkpoint inhibitors and oncolytic viruses, as well as advancements in BiTE technology, are essential to improving treatment efficacy. The future of BiTEs in uro-oncology lies in overcoming current limitations, optimising therapeutic strategies, and expanding clinical trials to solidify their role in cancer immunotherapy.
{"title":"Unlocking precision: Bispecific T cell engagers and the next frontier in uro-oncology","authors":"Joecelyn Kirani Tan , Sri Vidya Niharika Gullapalli , Pratima Chapagain , Aruni Ghose , Armand Grollemund , Alex Speechley , Maryam Hasanova , Sayali D. Shinde , Advaith Kandala , Akash Maniam , Ankit Jain , Sola Adeleke , Sara Elena Rebuzzi , Jeremy Yuen-Chun Teoh , Yüksel Ürün , Giuseppe Luigi Banna , Stergios Boussios","doi":"10.1016/j.critrevonc.2025.105039","DOIUrl":"10.1016/j.critrevonc.2025.105039","url":null,"abstract":"<div><div>Urological cancers, including prostate, bladder, renal, and testicular cancers, present significant challenges in terms of incidence, mortality, and treatment resistance. Immunotherapy, particularly bispecific T-cell engagers (BiTEs), has emerged as a promising therapeutic strategy, targeting tumor-specific antigens to activate T cells and enhance anti-tumor immunity. BiTEs, such as pasotuxizumab for prostate cancer, and CD3 ×B7-H3 BiTE for bladder cancer, demonstrate potential in overcoming the limitations of traditional therapies and immune checkpoint inhibitors. This review explores the application of BiTEs in urological cancers, highlighting their clinical outcomes, challenges, and future prospects. Although BiTEs offer significant advantages, including selective T-cell activation and low-dose efficacy, obstacles such as on-target off-tumor toxicity, the immunosuppressive tumour microenvironment (TME), and immune-related adverse effects need to be addressed for broader clinical success. Combination therapies with immune checkpoint inhibitors and oncolytic viruses, as well as advancements in BiTE technology, are essential to improving treatment efficacy. The future of BiTEs in uro-oncology lies in overcoming current limitations, optimising therapeutic strategies, and expanding clinical trials to solidify their role in cancer immunotherapy.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"217 ","pages":"Article 105039"},"PeriodicalIF":5.6,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582853","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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