Pub Date : 2025-12-09DOI: 10.1016/j.critrevonc.2025.105076
Xuejun Guo , Huaibo Zhang , Liqin Yao , Wenxue Ma
Pancreatic cancer remains one of the most lethal malignancies, characterized by rapid progression, late-stage diagnosis, and resistance to current therapies. A major contributor to its poor prognosis is the highly immunosuppressive tumor microenvironment (TME), where regulatory T cells (Tregs) suppressing effector T cells (Teffs). The ratio of Teffs to Tregs (Teff/Treg ratio) has emerged as a pivotal biomarker that reflects immune balance within the TME, with significant prognostic and therapeutic relevance. A low Teff/Treg ratio correlates with poor clinical outcomes, immunotherapy resistance, and tumor progression. Elucidating the mechanisms regulating that regulate this ratio such as immune checkpoint pathways, cytokine-mediated signaling, and stromal interactions offers promising avenues to restore anti-tumor immunity. This review critically evaluates the prognostic values of the Teff/Treg ratio in pancreatic cancer, highlights emerging strategies to rebalance this axis, and outlines current challenges and research gaps. Standardizing measurement methodologies and integrating Teff/Treg analysis into pancreatic cancer-specific research are essential next steps toward precision immunotherapy.
{"title":"Harnessing the effector-to-regulatory T cell ratio to advance prognosis and precision therapy in pancreatic cancer","authors":"Xuejun Guo , Huaibo Zhang , Liqin Yao , Wenxue Ma","doi":"10.1016/j.critrevonc.2025.105076","DOIUrl":"10.1016/j.critrevonc.2025.105076","url":null,"abstract":"<div><div>Pancreatic cancer remains one of the most lethal malignancies, characterized by rapid progression, late-stage diagnosis, and resistance to current therapies. A major contributor to its poor prognosis is the highly immunosuppressive tumor microenvironment (TME), where regulatory T cells (Tregs) suppressing effector T cells (Teffs). The ratio of Teffs to Tregs (Teff/Treg ratio) has emerged as a pivotal biomarker that reflects immune balance within the TME, with significant prognostic and therapeutic relevance. A low Teff/Treg ratio correlates with poor clinical outcomes, immunotherapy resistance, and tumor progression. Elucidating the mechanisms regulating that regulate this ratio such as immune checkpoint pathways, cytokine-mediated signaling, and stromal interactions offers promising avenues to restore anti-tumor immunity. This review critically evaluates the prognostic values of the Teff/Treg ratio in pancreatic cancer, highlights emerging strategies to rebalance this axis, and outlines current challenges and research gaps. Standardizing measurement methodologies and integrating Teff/Treg analysis into pancreatic cancer-specific research are essential next steps toward precision immunotherapy.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105076"},"PeriodicalIF":5.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145735276","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 : 2025-12-09DOI: 10.1016/j.critrevonc.2025.105080
Sarah J. Taylor, Charlie Gourley
Cyclin E1 is a critical mediator of cell cycle dynamics, controlling G1/S phase transition in complex with CDK2. Overexpression of cyclin E1 can lead to replication stress, DNA damage, and heightened genomic instability. This is associated with oncogenesis, and is frequently observed pan-cancer; but is particularly common in high grade serous ovarian cancer (HGSOC). HGSOC exhibits a genomic landscape dominated by structural variation and instability, with high cyclin E1 expression in up to 58 % and CCNE1 amplification in up to 30 % of cases. HGSOC therefore represents an exemplar setting for investigating cyclin E dysregulation in cancer. HGSOC patients with high tumour expression of cyclin E1, in combination with copy number amplification, experience particularly poor survival. Agents targeting CDK2, WEE1, and PYMKT1, and other cell cycle associated targets have shown strong preclinical activity in models of high cyclin E expression and CCNE1 amplification. Recent clinical trials have explored the efficacy and tolerability of these agents, particularly in biomarker selected cohorts. The WEE1 inhibitor adavosertib and the CDK2 inhibitor INCB123667 achieved response rates of 53 % and 33 % respectively in platinum-resistant ovarian cancer patients whose tumours overexpressed cyclin E1. Targeting of cyclin E dysregulation via a synthetic lethality approach is therefore a key area of focus for improving treatment strategies in HGSOC and other cancers with high unmet clinical need. In this review we discuss the functions of cyclin E1, mechanisms and consequences of dysregulation, and strategies for therapeutic exploitation of cyclin E1 dysregulated tumours, combining fundamental biology with clinical perspectives.
{"title":"Cyclin E1 as a driver of oncogenesis; high grade serous ovarian cancer as an exemplar","authors":"Sarah J. Taylor, Charlie Gourley","doi":"10.1016/j.critrevonc.2025.105080","DOIUrl":"10.1016/j.critrevonc.2025.105080","url":null,"abstract":"<div><div>Cyclin E1 is a critical mediator of cell cycle dynamics, controlling G1/S phase transition in complex with CDK2. Overexpression of cyclin E1 can lead to replication stress, DNA damage, and heightened genomic instability. This is associated with oncogenesis, and is frequently observed pan-cancer; but is particularly common in high grade serous ovarian cancer (HGSOC). HGSOC exhibits a genomic landscape dominated by structural variation and instability, with high cyclin E1 expression in up to 58 % and <em>CCNE1</em> amplification in up to 30 % of cases. HGSOC therefore represents an exemplar setting for investigating cyclin E dysregulation in cancer. HGSOC patients with high tumour expression of cyclin E1, in combination with copy number amplification, experience particularly poor survival. Agents targeting CDK2, WEE1, and PYMKT1, and other cell cycle associated targets have shown strong preclinical activity in models of high cyclin E expression and <em>CCNE1</em> amplification. Recent clinical trials have explored the efficacy and tolerability of these agents, particularly in biomarker selected cohorts. The WEE1 inhibitor adavosertib and the CDK2 inhibitor INCB123667 achieved response rates of 53 % and 33 % respectively in platinum-resistant ovarian cancer patients whose tumours overexpressed cyclin E1. Targeting of cyclin E dysregulation via a synthetic lethality approach is therefore a key area of focus for improving treatment strategies in HGSOC and other cancers with high unmet clinical need. In this review we discuss the functions of cyclin E1, mechanisms and consequences of dysregulation, and strategies for therapeutic exploitation of cyclin E1 dysregulated tumours, combining fundamental biology with clinical perspectives.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105080"},"PeriodicalIF":5.6,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145746093","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}
Breast cancer remains as one of the leading causes of mortality and morbidity among women worldwide, underscoring the need for a better understanding of breast cancer etiopathogenesis, effective new therapeutics and clinically actionable biomarkers. Pseudogenes, traditionally seen as nonfunctional sequences of DNA, are increasingly recognized to have important functions in physiology and disease, including in various cancers. Recently accumulating and expanding body of data has emphasized the potential role of pseudogenes in multiple aspects of breast cancer pathogenesis including their function as oncogenes or tumor suppressors to influence cellular proliferation, migration, invasion, apoptosis, angiogenesis, immune modulation, and maintenance of cancer stem cell properties. Moreover, expression of many pseudogenes has been shown to correlate with patient survival parameters and clinicopathologic characteristics of the tumor, making them excellent candidates as prognostic biomarkers. Pseudogene expression can also modulate responses of breast cancer to chemotherapeutic agents and antihormonal treatments, as well as radiotherapy, indicating their potential as treatment response biomarkers. Given their functions in breast cancer biology, pseudogenes can serve as novel targets for treatment. Here, the roles of pseudogenes in breast cancer are discussed in detail.
{"title":"Pseudogenes in breast cancer pathogenesis and their clinical utility","authors":"Isabel Kannampuzha , Farhad Ghasemi , Armen Parsyan","doi":"10.1016/j.critrevonc.2025.105078","DOIUrl":"10.1016/j.critrevonc.2025.105078","url":null,"abstract":"<div><div>Breast cancer remains as one of the leading causes of mortality and morbidity among women worldwide, underscoring the need for a better understanding of breast cancer etiopathogenesis, effective new therapeutics and clinically actionable biomarkers. Pseudogenes, traditionally seen as nonfunctional sequences of DNA, are increasingly recognized to have important functions in physiology and disease, including in various cancers. Recently accumulating and expanding body of data has emphasized the potential role of pseudogenes in multiple aspects of breast cancer pathogenesis including their function as oncogenes or tumor suppressors to influence cellular proliferation, migration, invasion, apoptosis, angiogenesis, immune modulation, and maintenance of cancer stem cell properties. Moreover, expression of many pseudogenes has been shown to correlate with patient survival parameters and clinicopathologic characteristics of the tumor, making them excellent candidates as prognostic biomarkers. Pseudogene expression can also modulate responses of breast cancer to chemotherapeutic agents and antihormonal treatments, as well as radiotherapy, indicating their potential as treatment response biomarkers. Given their functions in breast cancer biology, pseudogenes can serve as novel targets for treatment. Here, the roles of pseudogenes in breast cancer are discussed in detail.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105078"},"PeriodicalIF":5.6,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145727856","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 : 2025-12-08DOI: 10.1016/j.critrevonc.2025.105074
Elettra Merola , Maria Pina Dore , Giovanni Mario Pes , Giuseppe Fanciulli
Background
High-grade gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of tumors with poor prognosis, including grade 3 neuroendocrine tumors (NETs G3) and neuroendocrine carcinomas (NECs), which represent distinct entities with different clinical outcomes. Our aim was to systematically review the available clinical evidence on therapeutic strategies for sporadic, highly proliferative GEP-NENs. Methods: A systematic literature search was conducted using PubMed, Scopus, and Web of Science (last update: August 9, 2025). Endpoints included the evaluation of clinical outcomes from interventional trials and subgroup analysis comparing NET G3 with NEC. Results: A total of 2135 records were retrieved, with a final inclusion of 28 prospective trials (six randomized trials). Twelve trials exclusively enrolled NECs, one trial focused on NET G3, five provided NET G3/NEC subanalyses, ten included mixed populations without morphological stratification. Owing to the high risk of bias, a meta-analysis was not feasible. In NECs, the highest disease control was achieved with the CAPOXIRI–Bevacizumab regimen (disease control rate, DCR 78.9 %; median progression-free survival, PFS 18 months; overall survival, OS 30.5 months), but the cohort was small (n = 19) and toxicity substantial. Immunotherapy yielded disappointing results, either as monotherapy or in combination with a dual checkpoint blockade (median PFS: ∼2 months). Platinum-based chemotherapy proved poor for NET G3, whereas temozolomide/everolimus and peptide receptor radionuclide therapy offered clear benefits (DCR: 96.1 % and 70 %, respectively). Conclusions: High-grade GEP-NENs (particularly NET G3) remain an overlooked population in interventional studies. Progress in precision medicine requires the identification of molecular biomarkers to guide individualized therapy.
{"title":"High-grade gastro-entero-pancreatic neuroendocrine neoplasms: An overlooked population in interventional clinical trials. A systematic review","authors":"Elettra Merola , Maria Pina Dore , Giovanni Mario Pes , Giuseppe Fanciulli","doi":"10.1016/j.critrevonc.2025.105074","DOIUrl":"10.1016/j.critrevonc.2025.105074","url":null,"abstract":"<div><h3>Background</h3><div>High-grade gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of tumors with poor prognosis, including grade 3 neuroendocrine tumors (NETs G3) and neuroendocrine carcinomas (NECs), which represent distinct entities with different clinical outcomes. Our aim was to systematically review the available clinical evidence on therapeutic strategies for sporadic, highly proliferative GEP-NENs. <em>Methods:</em> A systematic literature search was conducted using PubMed, Scopus, and Web of Science (last update: August 9, 2025). Endpoints included the evaluation of clinical outcomes from interventional trials and subgroup analysis comparing NET G3 with NEC. <em>Results:</em> A total of 2135 records were retrieved, with a final inclusion of 28 prospective trials (six randomized trials). Twelve trials exclusively enrolled NECs, one trial focused on NET G3, five provided NET G3/NEC subanalyses, ten included mixed populations without morphological stratification. Owing to the high risk of bias, a meta-analysis was not feasible. In NECs, the highest disease control was achieved with the CAPOXIRI–Bevacizumab regimen (disease control rate, DCR 78.9 %; median progression-free survival, PFS 18 months; overall survival, OS 30.5 months), but the cohort was small (n = 19) and toxicity substantial. Immunotherapy yielded disappointing results, either as monotherapy or in combination with a dual checkpoint blockade (median PFS: ∼2 months). Platinum-based chemotherapy proved poor for NET G3, whereas temozolomide/everolimus and peptide receptor radionuclide therapy offered clear benefits (DCR: 96.1 % and 70 %, respectively). <em>Conclusions:</em> High-grade GEP-NENs (particularly NET G3) remain an overlooked population in interventional studies. Progress in precision medicine requires the identification of molecular biomarkers to guide individualized therapy.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105074"},"PeriodicalIF":5.6,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145727792","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 : 2025-12-06DOI: 10.1016/j.critrevonc.2025.105069
Salah Ameen Abdu , Wafa Ali Asaad , Muaadh Wdaan , Ning Li
Background
Sex-based differences in immune response and cancer biology may influence treatment outcomes with immunotherapy combinations. Comprehensive evidence regarding whether biological sex affects the efficacy of immune checkpoint inhibitor plus chemotherapy regimens remains incomplete.
Methods
Following PRISMA guidelines, we systematically searched five databases through May 2025 for randomized controlled trials comparing immune checkpoint inhibitors plus chemotherapy versus chemotherapy alone in any cancer type. We performed a comprehensive meta-analysis with sex-stratified survival data, subgroup analyses across cancer types and treatment regimens, meta-regression, interaction testing with false discovery rate correction, and publication bias assessment.
Results
Seventy-nine trials enrolling 50,046 patients (30,503 males, 19,543 females) met inclusion criteria. Combination therapy significantly improved survival in both sexes: overall survival hazard ratios were 0.76 (95 % CI 0.73–0.78) in males and 0.78 (95 % CI 0.75–0.81) in females, representing 24 % and 22 % mortality reductions, respectively. Progression-free survival improved by 39 % in males (HR 0.61, 95 % CI 0.57–0.64) and 34 % in females (HR 0.66, 95 % CI 0.62–0.70). Overlapping confidence intervals and formal interaction testing revealed no statistically significant sex-based differences across cancer types, immunotherapy agents, histological subtypes, or chemotherapy backbones.
Conclusions
Immune checkpoint inhibitors with chemotherapy provide significant and equivalent survival benefits for both male and female patients across cancer types. Treatment decisions should therefore be guided by tumor characteristics, not patient sex. These results support equitable treatment access and highlight the necessity for continued sex-stratified data reporting in clinical trials.
背景：基于性别的免疫反应和癌症生物学差异可能影响免疫治疗组合的治疗结果。关于生理性别是否影响免疫检查点抑制剂加化疗方案的疗效的综合证据仍不完整。方法：遵循PRISMA指南，我们系统地检索了截至2025年5月的5个数据库，以比较免疫检查点抑制剂加化疗与单独化疗在任何癌症类型中的随机对照试验。我们进行了一项综合荟萃分析，包括按性别分层的生存数据、跨癌症类型和治疗方案的亚组分析、荟萃回归、带错误发现率校正的相互作用检验和发表偏倚评估。结果：79项试验纳入50,046例患者（男性30,503例，女性19,543例）符合纳入标准。联合治疗显著提高了两性的生存率：男性的总生存风险比为0.76 (95% CI 0.73-0.78)，女性的总生存风险比为0.78 (95% CI 0.75-0.81)，分别代表死亡率降低24%和22%。无进展生存率男性提高39% (HR 0.61, 95% CI 0.57-0.64)，女性提高34% （HR 0.66, 95% CI 0.62-0.70）。重叠置信区间和正式的相互作用测试显示，在癌症类型、免疫治疗药物、组织学亚型或化疗骨干之间，没有统计学上显著的基于性别的差异。结论：免疫检查点抑制剂联合化疗对不同癌症类型的男性和女性患者提供了显著且相同的生存益处。因此，治疗决定应以肿瘤特征为指导，而不是患者的性别。这些结果支持公平获得治疗，并强调在临床试验中继续按性别分层报告数据的必要性。
{"title":"Sex differences in immunotherapy plus chemotherapy: A systematic review and meta-analysis","authors":"Salah Ameen Abdu , Wafa Ali Asaad , Muaadh Wdaan , Ning Li","doi":"10.1016/j.critrevonc.2025.105069","DOIUrl":"10.1016/j.critrevonc.2025.105069","url":null,"abstract":"<div><h3>Background</h3><div>Sex-based differences in immune response and cancer biology may influence treatment outcomes with immunotherapy combinations. Comprehensive evidence regarding whether biological sex affects the efficacy of immune checkpoint inhibitor plus chemotherapy regimens remains incomplete.</div></div><div><h3>Methods</h3><div>Following PRISMA guidelines, we systematically searched five databases through May 2025 for randomized controlled trials comparing immune checkpoint inhibitors plus chemotherapy versus chemotherapy alone in any cancer type. We performed a comprehensive meta-analysis with sex-stratified survival data, subgroup analyses across cancer types and treatment regimens, meta-regression, interaction testing with false discovery rate correction, and publication bias assessment.</div></div><div><h3>Results</h3><div>Seventy-nine trials enrolling 50,046 patients (30,503 males, 19,543 females) met inclusion criteria. Combination therapy significantly improved survival in both sexes: overall survival hazard ratios were 0.76 (95 % CI 0.73–0.78) in males and 0.78 (95 % CI 0.75–0.81) in females, representing 24 % and 22 % mortality reductions, respectively. Progression-free survival improved by 39 % in males (HR 0.61, 95 % CI 0.57–0.64) and 34 % in females (HR 0.66, 95 % CI 0.62–0.70). Overlapping confidence intervals and formal interaction testing revealed no statistically significant sex-based differences across cancer types, immunotherapy agents, histological subtypes, or chemotherapy backbones.</div></div><div><h3>Conclusions</h3><div>Immune checkpoint inhibitors with chemotherapy provide significant and equivalent survival benefits for both male and female patients across cancer types. Treatment decisions should therefore be guided by tumor characteristics, not patient sex. These results support equitable treatment access and highlight the necessity for continued sex-stratified data reporting in clinical trials.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105069"},"PeriodicalIF":5.6,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710521","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}
Colorectal cancer, a significant contributor to cancer-related fatalities worldwide, develops due to the complex interaction between tumor cells and their immediate environment. CCL2, a type of chemokine, plays a significant role in colorectal cancer advancement through its impact on immune cell recruitment, inflammation, and metastasis. The receptor CCR2 mediates CCL2's function in directing the migration of tumor-associated macrophages (TAMs), which in turn promotes epithelial-mesenchymal transition (EMT), angiogenesis, and immune evasion. According to this narrative review, the CCL2/CCR2 axis plays a key role in both the tumor microenvironment and the metastasis of CRC. The study investigates the therapeutic possibilities of CCL2 targeting, alongside creative bioengineering methods such as siRNA and miRNA therapies, aptamers, small molecules, and CRISPR technologies. Thanks to recent developments in bioinformatics and molecular therapies, it's now possible to explore innovative strategies to block the CCL2/CCR2 pathway, potentially leading to better alternatives for treating colorectal cancer. The main focus of future studies should be on addressing therapeutic resistance, enhancing combination therapies, and identifying predictive biomarkers to enhance treatment efficacy and patient results. The study reveals complex molecular interactions regulated by CCL2, thus offering a foundation for innovative therapeutic approaches to colorectal cancer.
{"title":"Targeting the CCL2/CCR2 axis in colorectal cancer: Immunopharmacological perspectives and therapeutic strategies","authors":"Fatemeh Hajibabaie , Navid Abedpoor , Bahareh Maleki , Maryam Boshtam , Nasim Shenavar , Ali Zarrabi , Mina Babakhani , Mehran Sharifi , Laleh Shariati , Ilnaz Rahimmanesh , Marco Cordani","doi":"10.1016/j.critrevonc.2025.105072","DOIUrl":"10.1016/j.critrevonc.2025.105072","url":null,"abstract":"<div><div>Colorectal cancer, a significant contributor to cancer-related fatalities worldwide, develops due to the complex interaction between tumor cells and their immediate environment. CCL2, a type of chemokine, plays a significant role in colorectal cancer advancement through its impact on immune cell recruitment, inflammation, and metastasis. The receptor CCR2 mediates CCL2's function in directing the migration of tumor-associated macrophages (TAMs), which in turn promotes epithelial-mesenchymal transition (EMT), angiogenesis, and immune evasion. According to this narrative review, the CCL2/CCR2 axis plays a key role in both the tumor microenvironment and the metastasis of CRC. The study investigates the therapeutic possibilities of CCL2 targeting, alongside creative bioengineering methods such as siRNA and miRNA therapies, aptamers, small molecules, and CRISPR technologies. Thanks to recent developments in bioinformatics and molecular therapies, it's now possible to explore innovative strategies to block the CCL2/CCR2 pathway, potentially leading to better alternatives for treating colorectal cancer. The main focus of future studies should be on addressing therapeutic resistance, enhancing combination therapies, and identifying predictive biomarkers to enhance treatment efficacy and patient results. The study reveals complex molecular interactions regulated by CCL2, thus offering a foundation for innovative therapeutic approaches to colorectal cancer.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105072"},"PeriodicalIF":5.6,"publicationDate":"2025-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145710509","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 : 2025-12-05DOI: 10.1016/j.critrevonc.2025.105071
Soraia Macari , Jôice Dias Corrêa , Victor Zanetti Drumond , Breno Amaral Rocha , Paula Alves da Silva Rocha , Lucas Guimarães Abreu , François Côme Ferré , Benjamin P.J. Fournier , José Alcides Almeida de Arruda , Tarcília Aparecida Silva
Since the 1980s, aromatase inhibitors (AI) have been a cornerstone in the management of hormone receptor-positive breast cancer. However, because of their frequent co-prescription with antiresorptive agents, concerns have been raised regarding the potential contribution of AI to medication-related osteonecrosis of the jaw (MRONJ). We conducted a scoping review to investigate the possible association between AI use and MRONJ. Electronic searches were performed across five databases and supplemented with manual screening and gray literature. Observational studies and clinical trials were included. Fifty-four studies comprising 1,613,480 individuals (45,121 AI users) from 17 countries were analyzed. Most samples consisted of women with breast cancer/metastatic breast cancer in pre- and/or postmenopausal stages. Letrozole was the most frequently prescribed AI, followed by anastrozole and exemestane. MRONJ was reported in 43 studies, with 1147 cases among 45,121 AI users (2.5 % of AI users in the included samples), the majority of whom were concomitantly treated with zoledronic acid and/or denosumab. Three studies documented MRONJ in patients receiving AI monotherapy. Data demonstrate the difficulty of disentangling the effects of AI from those of antiresorptive therapy in MRONJ pathogenesis. Future research should consider AI as potential confounders in analytical studies to clarify their independent contribution, if any, to observed MRONJ occurrences.
{"title":"Aromatase inhibitors and medication-related osteonecrosis of the jaw: Friends, foes, or bystanders?","authors":"Soraia Macari , Jôice Dias Corrêa , Victor Zanetti Drumond , Breno Amaral Rocha , Paula Alves da Silva Rocha , Lucas Guimarães Abreu , François Côme Ferré , Benjamin P.J. Fournier , José Alcides Almeida de Arruda , Tarcília Aparecida Silva","doi":"10.1016/j.critrevonc.2025.105071","DOIUrl":"10.1016/j.critrevonc.2025.105071","url":null,"abstract":"<div><div>Since the 1980s, aromatase inhibitors (AI) have been a cornerstone in the management of hormone receptor-positive breast cancer. However, because of their frequent co-prescription with antiresorptive agents, concerns have been raised regarding the potential contribution of AI to medication-related osteonecrosis of the jaw (MRONJ). We conducted a scoping review to investigate the possible association between AI use and MRONJ. Electronic searches were performed across five databases and supplemented with manual screening and gray literature. Observational studies and clinical trials were included. Fifty-four studies comprising 1,613,480 individuals (45,121 AI users) from 17 countries were analyzed. Most samples consisted of women with breast cancer/metastatic breast cancer in pre- and/or postmenopausal stages. Letrozole was the most frequently prescribed AI, followed by anastrozole and exemestane. MRONJ was reported in 43 studies, with 1147 cases among 45,121 AI users (2.5 % of AI users in the included samples), the majority of whom were concomitantly treated with zoledronic acid and/or denosumab. Three studies documented MRONJ in patients receiving AI monotherapy. Data demonstrate the difficulty of disentangling the effects of AI from those of antiresorptive therapy in MRONJ pathogenesis. Future research should consider AI as potential confounders in analytical studies to clarify their independent contribution, if any, to observed MRONJ occurrences.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105071"},"PeriodicalIF":5.6,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145703431","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 : 2025-12-05DOI: 10.1016/j.critrevonc.2025.105070
Shuwen Li, Zeli Li
Ferroptosis—an iron-dependent, lipid peroxidation–driven cell death—has emerged as a central regulator of tumor biology and antitumor immunity in prostate, bladder, and renal cancers. Beyond direct cytotoxicity, it bidirectionally reshapes the tumor immune microenvironment. CD8 + and NK cells induce ferroptosis via IFN-γ–mediated suppression of system Xc−, whereas ferroptotic cells release DAMPs and antigens that mature dendritic cells and activate T cells. Conversely, ferroptosis in effector lymphocytes and tumor antioxidant, metabolic, and myeloid programs can enforce immune suppression. mRNA and lncRNA ferroptosis signatures stratify prognosis and immunotherapy response, often separating checkpoint-restrained “hot” tumors from immune-excluded/desert states. Mechanistic nodes (SLC7A11, GPX4, PRMT5, ATF4/NUPR1) and stromal/macrophage circuits link ferroptosis resistance to immune evasion. Emerging strategies combine ferroptosis induction with checkpoint blockade, adoptive cellular therapies, nano-delivery, and microenvironment reprogramming to convert “cold” disease into durable responders.
{"title":"The crosstalk between ferroptosis and the immune system in urological cancers: Mechanisms, prognostic value, and therapeutic implications","authors":"Shuwen Li, Zeli Li","doi":"10.1016/j.critrevonc.2025.105070","DOIUrl":"10.1016/j.critrevonc.2025.105070","url":null,"abstract":"<div><div>Ferroptosis—an iron-dependent, lipid peroxidation–driven cell death—has emerged as a central regulator of tumor biology and antitumor immunity in prostate, bladder, and renal cancers. Beyond direct cytotoxicity, it bidirectionally reshapes the tumor immune microenvironment. CD8 + and NK cells induce ferroptosis via IFN-γ–mediated suppression of system Xc−, whereas ferroptotic cells release DAMPs and antigens that mature dendritic cells and activate T cells. Conversely, ferroptosis in effector lymphocytes and tumor antioxidant, metabolic, and myeloid programs can enforce immune suppression. mRNA and lncRNA ferroptosis signatures stratify prognosis and immunotherapy response, often separating checkpoint-restrained “hot” tumors from immune-excluded/desert states. Mechanistic nodes (SLC7A11, GPX4, PRMT5, ATF4/NUPR1) and stromal/macrophage circuits link ferroptosis resistance to immune evasion. Emerging strategies combine ferroptosis induction with checkpoint blockade, adoptive cellular therapies, nano-delivery, and microenvironment reprogramming to convert “cold” disease into durable responders.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105070"},"PeriodicalIF":5.6,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145703430","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 : 2025-12-05DOI: 10.1016/j.critrevonc.2025.105060
Yu Tian , Kaobin Ouyang , Hongsheng Wu , Haojie Liao , Lingjuan He , Tingting Luo , Keqiang Ma , Xiaowen Mao , Furong Wang , Hailin Xiong
Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality due to profound heterogeneity and persistent therapeutic resistance. This review summarizes recent mechanistic advances showing how noncoding RNAs (ncRNAs)—including lncRNAs and circRNAs—cooperate with RNA-binding proteins (RBPs) to regulate ferroptosis, autophagy, lipid metabolism, immune evasion, and transcriptional programs. We highlight emerging principles involving RNA chemical modifications, structural elements, and liquid–liquid phase separation that define the specificity of ncRNA–RBP interactions. Recent multi-omics and spatial profiling technologies are also discussed for their role in revealing resistance-associated ncRNA–protein networks. Importantly, this review integrates these findings to outline actionable therapeutic opportunities and the translational potential of targeting ncRNA–RBP axes, emphasizing their relevance to precision oncology. By defining the key regulatory circuits that drive adaptive resistance, this work provides a conceptual framework that may guide biomarker development and personalized treatment strategies in HCC.
{"title":"Adaptive drug resistance mechanisms driven by non-coding RNA–protein interaction networks in hepatocellular carcinoma","authors":"Yu Tian , Kaobin Ouyang , Hongsheng Wu , Haojie Liao , Lingjuan He , Tingting Luo , Keqiang Ma , Xiaowen Mao , Furong Wang , Hailin Xiong","doi":"10.1016/j.critrevonc.2025.105060","DOIUrl":"10.1016/j.critrevonc.2025.105060","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality due to profound heterogeneity and persistent therapeutic resistance. This review summarizes recent mechanistic advances showing how noncoding RNAs (ncRNAs)—including lncRNAs and circRNAs—cooperate with RNA-binding proteins (RBPs) to regulate ferroptosis, autophagy, lipid metabolism, immune evasion, and transcriptional programs. We highlight emerging principles involving RNA chemical modifications, structural elements, and liquid–liquid phase separation that define the specificity of ncRNA–RBP interactions. Recent multi-omics and spatial profiling technologies are also discussed for their role in revealing resistance-associated ncRNA–protein networks. Importantly, this review integrates these findings to outline actionable therapeutic opportunities and the translational potential of targeting ncRNA–RBP axes, emphasizing their relevance to precision oncology. By defining the key regulatory circuits that drive adaptive resistance, this work provides a conceptual framework that may guide biomarker development and personalized treatment strategies in HCC.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105060"},"PeriodicalIF":5.6,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145703418","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 : 2025-12-04DOI: 10.1016/j.critrevonc.2025.105066
Dehuan Zhang , Yuehan Zhao, Dandan Guo
The interplay between the tumor microenvironment and metabolic cell death pathways has emerged as a critical focus in contemporary cancer research. This comprehensive review examines the mechanistic interactions between these processes and evaluates their therapeutic and diagnostic implications in cancer management. Following Hanahan and Weinberg's seminal characterization of cancer hallmarks in 2011, substantial experimental and clinical evidence has accumulated, expanding our understanding of tumor biology. This review specifically addresses several key aspects: metabolic perturbations within the TME and their interactions with ferroptosis, cuproptosis, and disulfidptosis pathways; therapeutic agents and combinatorial approaches targeting these distinct metabolic cell death mechanisms; advanced delivery systems, particularly nanocarrier-based platforms, for enhancing metabolic cell death-inducing therapeutic strategies. It also points out the limitations of various therapeutic approaches that induce metabolic death in tumor cells, and predicts the directions that can be focused on exploring in the future.
{"title":"Application and potential of the tumor microenvironment, ferroptosis, cuproptosis, and disulfidptosis in cancer treatment and monitoring","authors":"Dehuan Zhang , Yuehan Zhao, Dandan Guo","doi":"10.1016/j.critrevonc.2025.105066","DOIUrl":"10.1016/j.critrevonc.2025.105066","url":null,"abstract":"<div><div>The interplay between the tumor microenvironment and metabolic cell death pathways has emerged as a critical focus in contemporary cancer research. This comprehensive review examines the mechanistic interactions between these processes and evaluates their therapeutic and diagnostic implications in cancer management. Following Hanahan and Weinberg's seminal characterization of cancer hallmarks in 2011, substantial experimental and clinical evidence has accumulated, expanding our understanding of tumor biology. This review specifically addresses several key aspects: metabolic perturbations within the TME and their interactions with ferroptosis, cuproptosis, and disulfidptosis pathways; therapeutic agents and combinatorial approaches targeting these distinct metabolic cell death mechanisms; advanced delivery systems, particularly nanocarrier-based platforms, for enhancing metabolic cell death-inducing therapeutic strategies. It also points out the limitations of various therapeutic approaches that induce metabolic death in tumor cells, and predicts the directions that can be focused on exploring in the future.</div></div>","PeriodicalId":11358,"journal":{"name":"Critical reviews in oncology/hematology","volume":"218 ","pages":"Article 105066"},"PeriodicalIF":5.6,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696516","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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