Pub Date : 2025-09-24DOI: 10.1016/j.bbcan.2025.189460
Jian Wang , Huihui Xiao , Siqian Cui , Chunrong Wu , Debing Xiang
Neutrophils play a multifaceted and dynamically evolving role in the progression of inflammation-driven colorectal cancer (CRC). This review summarizes the functional reprogramming and phenotypic polarization of neutrophils under chronic inflammatory conditions, with a particular focus on their contribution to tumor immune microenvironment remodeling. Specifically, we highlight the role of neutrophil extracellular traps (NETs), released through NETosis, in establishing immunosuppressive networks and reshaping the pro-metastatic stromal niche. The review further discusses the reciprocal interactions between neutrophils and the tumor microenvironment, as well as the impact of metabolic reprogramming and gut microbiota crosstalk on inflammation-to-cancer transition. By systematically outlining the mechanisms through which neutrophils influence inflammation-associated CRC, this review aims to provide conceptual insights and a framework for future research and therapeutic intervention strategies.
{"title":"The bridging role of neutrophils in the progression of inflammation-induced colorectal cancer","authors":"Jian Wang , Huihui Xiao , Siqian Cui , Chunrong Wu , Debing Xiang","doi":"10.1016/j.bbcan.2025.189460","DOIUrl":"10.1016/j.bbcan.2025.189460","url":null,"abstract":"<div><div>Neutrophils play a multifaceted and dynamically evolving role in the progression of inflammation-driven colorectal cancer (CRC). This review summarizes the functional reprogramming and phenotypic polarization of neutrophils under chronic inflammatory conditions, with a particular focus on their contribution to tumor immune microenvironment remodeling. Specifically, we highlight the role of neutrophil extracellular traps (NETs), released through NETosis, in establishing immunosuppressive networks and reshaping the pro-metastatic stromal niche. The review further discusses the reciprocal interactions between neutrophils and the tumor microenvironment, as well as the impact of metabolic reprogramming and gut microbiota crosstalk on inflammation-to-cancer transition. By systematically outlining the mechanisms through which neutrophils influence inflammation-associated CRC, this review aims to provide conceptual insights and a framework for future research and therapeutic intervention strategies.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189460"},"PeriodicalIF":9.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145180777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-24DOI: 10.1016/j.bbcan.2025.189459
Tingting Zhang , Hengtong Han , Tianying Zhang , Yating Zhang , Libin Ma , Ze Yang , Yong-xun Zhao
Oncogenes enhance cancer development, and their specific activating mutations exemplify the mechanisms that initiate and mediate thyroid cancer (TC) progression. Research has predominantly focused on how oncogenes promote the development of different TC subtypes by influencing the downstream signaling pathways. Targeted therapies show significant efficacy; however, they often induce drug resistance through feedback activation or compensatory signaling bypasses. Recent evidence indicates that thyroid oncogenes initiate and mediate TC progression, and contribute to drug resistance in distinct TC subtypes through induced metabolic reprogramming and immune microenvironment remodeling. Hence, we propose the concept “Oncogene-Metabolism-Immunity axis.” We discussed the molecular mechanisms by which oncogene-driven metabolic reprogramming and tumor immune microenvironment Remodeling (TIME), and their mutual interactions, induce TC progression, drug resistance, and immune evasion. Finally, we systematically evaluated and summarized potential strategies targeting key oncogenes, metabolic catalysts, immune checkpoints (ICs), and combination therapies to enhance the efficacy of targeted treatments for TC and overcome drug resistance.
{"title":"Oncogenic mutation-driven metabolism-immunity regulatory axis: Potential prospects for thyroid cancer precision therapy","authors":"Tingting Zhang , Hengtong Han , Tianying Zhang , Yating Zhang , Libin Ma , Ze Yang , Yong-xun Zhao","doi":"10.1016/j.bbcan.2025.189459","DOIUrl":"10.1016/j.bbcan.2025.189459","url":null,"abstract":"<div><div>Oncogenes enhance cancer development, and their specific activating mutations exemplify the mechanisms that initiate and mediate thyroid cancer (TC) progression. Research has predominantly focused on how oncogenes promote the development of different TC subtypes by influencing the downstream signaling pathways. Targeted therapies show significant efficacy; however, they often induce drug resistance through feedback activation or compensatory signaling bypasses. Recent evidence indicates that thyroid oncogenes initiate and mediate TC progression, and contribute to drug resistance in distinct TC subtypes through induced metabolic reprogramming and immune microenvironment remodeling. Hence, we propose the concept “Oncogene-Metabolism-Immunity axis.” We discussed the molecular mechanisms by which oncogene-driven metabolic reprogramming and tumor immune microenvironment Remodeling (TIME), and their mutual interactions, induce TC progression, drug resistance, and immune evasion. Finally, we systematically evaluated and summarized potential strategies targeting key oncogenes, metabolic catalysts, immune checkpoints (ICs), and combination therapies to enhance the efficacy of targeted treatments for TC and overcome drug resistance.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189459"},"PeriodicalIF":9.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145156212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-23DOI: 10.1016/j.bbcan.2025.189458
Zhenting Lu , Midie Xu , Junzhe Tang , Xinyi Wang , Xinxiang Li , Qingguo Li
Tumor-associated macrophages (TAMs) are a central component of the tumor microenvironment and exert dual, context-dependent effects on cancer progression. This review synthesizes the mechanisms that govern TAM polarization, their bidirectional crosstalk with tumor and stromal cells, and the consequences of metabolic reprogramming. Molecular and metabolic circuits that shape TAM phenotypes and sustain immune suppression are highlighted, and therapeutic strategies targeting TAM checkpoints, metabolism, and lineage pathways are summarized. To integrate immunometabolism with single-cell and spatial profiling, we introduce a Metabolic-Spatial-Functional Axis that links dominant metabolic programs, anatomic niches, and measurable effector functions. This framework organizes TAM heterogeneity and prioritizes biomarker-guided therapeutic combinations with clear translational readouts. Collectively, these advances support precision approaches that reprogram or constrain TAMs to enhance antitumor immunity and overcome therapeutic resistance.
{"title":"Targetable axes of tumor-associated macrophages: An MSF framework for precision immunotherapy","authors":"Zhenting Lu , Midie Xu , Junzhe Tang , Xinyi Wang , Xinxiang Li , Qingguo Li","doi":"10.1016/j.bbcan.2025.189458","DOIUrl":"10.1016/j.bbcan.2025.189458","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs) are a central component of the tumor microenvironment and exert dual, context-dependent effects on cancer progression. This review synthesizes the mechanisms that govern TAM polarization, their bidirectional crosstalk with tumor and stromal cells, and the consequences of metabolic reprogramming. Molecular and metabolic circuits that shape TAM phenotypes and sustain immune suppression are highlighted, and therapeutic strategies targeting TAM checkpoints, metabolism, and lineage pathways are summarized. To integrate immunometabolism with single-cell and spatial profiling, we introduce a Metabolic-Spatial-Functional Axis that links dominant metabolic programs, anatomic niches, and measurable effector functions. This framework organizes TAM heterogeneity and prioritizes biomarker-guided therapeutic combinations with clear translational readouts. Collectively, these advances support precision approaches that reprogram or constrain TAMs to enhance antitumor immunity and overcome therapeutic resistance.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189458"},"PeriodicalIF":9.7,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145152216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1016/j.bbcan.2025.189454
Helin Kang , Xi Liu , Dan Ge , Yu Zeng
Bladder cancer (BC), characterized by remarkable tumor heterogeneity, remains a challenging malignancy with limited therapeutic options. Emerging three-dimensional (3D) organoid models are transforming our understanding of BC biology by closely mimicking the complex tumor microenvironment (TME) and cellular interactions, far surpassing traditional two-dimensional (2D) cell culture systems. This review underscores the innovative advances in bladder cancer organoid technology, emphasizing their unique strengths in capturing intratumoral heterogeneity, enhancing drug sensitivity assessments, and facilitating personalized treatment approaches. We discuss diverse organoid systems, including spheroids, assembloids, and patient-derived organoid xenografts (PDOX), highlighting their exceptional ability to replicate individual patient tumor profiles. Furthermore, we explore integrated organoid-on-chip cultivation techniques incorporating 3D bioprinting and microfluidics, which notably improve precision, reproducibility, and scalability in organoid-based drug screening platforms. We advocate for optimized organoid cultivation protocols and synergistic integration with high-throughput analytical technologies, aiming ultimately to accelerate regimen breakthroughs in personalized medicine for bladder cancer patients.
{"title":"Revolutionizing bladder cancer research: Harnessing 3D organoid technology to decode tumor heterogeneity and propel personalized therapeutics","authors":"Helin Kang , Xi Liu , Dan Ge , Yu Zeng","doi":"10.1016/j.bbcan.2025.189454","DOIUrl":"10.1016/j.bbcan.2025.189454","url":null,"abstract":"<div><div>Bladder cancer (BC), characterized by remarkable tumor heterogeneity, remains a challenging malignancy with limited therapeutic options. Emerging three-dimensional (3D) organoid models are transforming our understanding of BC biology by closely mimicking the complex tumor microenvironment (TME) and cellular interactions, far surpassing traditional two-dimensional (2D) cell culture systems. This review underscores the innovative advances in bladder cancer organoid technology, emphasizing their unique strengths in capturing intratumoral heterogeneity, enhancing drug sensitivity assessments, and facilitating personalized treatment approaches. We discuss diverse organoid systems, including spheroids, assembloids, and patient-derived organoid xenografts (PDOX), highlighting their exceptional ability to replicate individual patient tumor profiles. Furthermore, we explore integrated organoid-on-chip cultivation techniques incorporating 3D bioprinting and microfluidics, which notably improve precision, reproducibility, and scalability in organoid-based drug screening platforms. We advocate for optimized organoid cultivation protocols and synergistic integration with high-throughput analytical technologies, aiming ultimately to accelerate regimen breakthroughs in personalized medicine for bladder cancer patients.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189454"},"PeriodicalIF":9.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Spatial transcriptomics (ST) plays a pivotal role in cancer research, offering a unique perspective on gene expression within the cancer microenvironment, further revolutionizing our current understanding of the subject. From addressing the limitations of traditional bulk RNA sequencing by preserving spatial context, this review discusses the importance of integrating machine learning (ML), artificial intelligence (AI), and statistical methods for interpreting ST data within oncology. Herein, we use examples from studies involving Raf kinase inhibitor protein (RKIP) and Ying Yang 1 (YY1) to illustrate applications for some of the ST techniques discussed. We explore how applying supervised learning techniques, such as Support Vector Machines (SVMs) and Random Forests (RFs), can significantly help further cancer classification and prediction of clinical outcomes and advance personalized medicine. Additionally, exploring unsupervised learning approaches like clustering and dimensionality reduction methods (PCA, t-SNE, UMAP) allows us to see hidden structures in ST data that may be overlooked. This review discusses recent tools and techniques that have been introduced within the last few years, underlining the transformation brought into ST by ML, AI, and statistical methods that provide new insight into oncogenic drivers such as YY1 and RKIP, cancer heterogeneity, and avenues for personalized medicine approaches in cancer treatment.
{"title":"Advances in artificial intelligence for spatial transcriptomics in cancer: Special focus on Yin Yang 1 (YY1) and Raf kinase inhibitor protein (RKIP)","authors":"Lekhya Dommalapati , Rachael Guenter , Yuvasri Golivi , Swapna Priya Ganji , Tatekalva Sandhya , Ganji Purnachandra Nagaraju , Madhu Sudhana Saddala","doi":"10.1016/j.bbcan.2025.189456","DOIUrl":"10.1016/j.bbcan.2025.189456","url":null,"abstract":"<div><div>Spatial transcriptomics (ST) plays a pivotal role in cancer research, offering a unique perspective on gene expression within the cancer microenvironment, further revolutionizing our current understanding of the subject. From addressing the limitations of traditional bulk RNA sequencing by preserving spatial context, this review discusses the importance of integrating machine learning (ML), artificial intelligence (AI), and statistical methods for interpreting ST data within oncology. Herein, we use examples from studies involving Raf kinase inhibitor protein (RKIP) and Ying Yang 1 (YY1) to illustrate applications for some of the ST techniques discussed. We explore how applying supervised learning techniques, such as Support Vector Machines (SVMs) and Random Forests (RFs), can significantly help further cancer classification and prediction of clinical outcomes and advance personalized medicine. Additionally, exploring unsupervised learning approaches like clustering and dimensionality reduction methods (PCA, t-SNE, UMAP) allows us to see hidden structures in ST data that may be overlooked. This review discusses recent tools and techniques that have been introduced within the last few years, underlining the transformation brought into ST by ML, AI, and statistical methods that provide new insight into oncogenic drivers such as YY1 and RKIP, cancer heterogeneity, and avenues for personalized medicine approaches in cancer treatment.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189456"},"PeriodicalIF":9.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-22DOI: 10.1016/j.bbcan.2025.189447
Suman Pakhira , Subhadip Kundu , Sib Sankar Roy
Metabolic reprogramming is a defining characteristic of cancer cells as they undergo multistage development. Cancer cells dynamically adjust their metabolism to aid their survival and to retain their malignant traits within the adverse tumour microenvironment (TME). Fatty acid oxidation (FAO) is a major source of cellular bioenergy, making it a key player in driving cancer cell growth. Over the past few years, an accumulating body of literature has shed light on the role of dysregulated FAO in cancer progression. Besides energy production, FAO also plays a protective role by mitigating lipotoxicity-induced cell death and preventing oxidative stress through NADPH production. Moreover, FAO is intricately linked with numerous critical signaling pathways, substantiating its importance as a pivotal metabolic adaptation in cancer cells. In the TME, various intrinsic and extrinsic factors continuously modulate the behaviour of cancer cells, including their metabolic attributes, such as the activation of FAO. Additionally, alterations in FAO within non-cancerous stromal cells also play a critical role in orchestrating the tumor progression. Despite the emerging recognition of FAO's significance in cancer biology, the precise molecular mechanisms underlying its dysregulation within the TME remain poorly understood. Given the pivotal role of FAO in bioenergetically priming the tumor progression, its aberrant regulation has become a focal point of cancer research, offering potential avenues for novel therapeutic strategies. This review provides an overview of recent advances in understanding how different microenvironmental factors modulate FAO to influence tumor progression.
{"title":"The role of fatty acid oxidation in metabolic crosstalk between tumor cells and associated factors in the microenvironment","authors":"Suman Pakhira , Subhadip Kundu , Sib Sankar Roy","doi":"10.1016/j.bbcan.2025.189447","DOIUrl":"10.1016/j.bbcan.2025.189447","url":null,"abstract":"<div><div>Metabolic reprogramming is a defining characteristic of cancer cells as they undergo multistage development. Cancer cells dynamically adjust their metabolism to aid their survival and to retain their malignant traits within the adverse tumour microenvironment (TME). Fatty acid oxidation (FAO) is a major source of cellular bioenergy, making it a key player in driving cancer cell growth. Over the past few years, an accumulating body of literature has shed light on the role of dysregulated FAO in cancer progression. Besides energy production, FAO also plays a protective role by mitigating lipotoxicity-induced cell death and preventing oxidative stress through NADPH production. Moreover, FAO is intricately linked with numerous critical signaling pathways, substantiating its importance as a pivotal metabolic adaptation in cancer cells. In the TME, various intrinsic and extrinsic factors continuously modulate the behaviour of cancer cells, including their metabolic attributes, such as the activation of FAO. Additionally, alterations in FAO within non-cancerous stromal cells also play a critical role in orchestrating the tumor progression. Despite the emerging recognition of FAO's significance in cancer biology, the precise molecular mechanisms underlying its dysregulation within the TME remain poorly understood. Given the pivotal role of FAO in bioenergetically priming the tumor progression, its aberrant regulation has become a focal point of cancer research, offering potential avenues for novel therapeutic strategies. This review provides an overview of recent advances in understanding how different microenvironmental factors modulate FAO to influence tumor progression.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189447"},"PeriodicalIF":9.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145139696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-21DOI: 10.1016/j.bbcan.2025.189457
Luca Fabris , Yahima Frión-Herrera , Massimiliano Cadamuro , Elena Campello , Paolo Simioni
Cholangiocarcinoma (CCA) is the liver malignancy with the most rapid increase in incidence and lethality in recent years. Venous thromboembolism (VTE) is a common complication of the cancer-associated hypercoagulable state, which may incite tumor progression and dissemination, thereby increasing cancer-related morbidity and mortality. Compared to other cancer types, occurrence of VTE in CCA has been underestimated, though recent evidence indicates it may behave as prognostic factor of worst outcome. Given the need for novel predictive scores and treatment approaches when VTE occurs, identifying subgroups of patients with CCA who would benefit from thromboprophylaxis without increasing the risk of bleeding is a crucial but still neglected aspect of the management. The aim of this review is to summarize current observations on the clinical significance, prediction, risk assessment and the underlying mechanisms of cancer-induced thrombogenesis in CCA, as well as to identify research areas ripe for prioritization in the near future.
{"title":"Cancer-associated thrombosis in cholangiocarcinoma: Exploring a phenotype of tumor aggressiveness","authors":"Luca Fabris , Yahima Frión-Herrera , Massimiliano Cadamuro , Elena Campello , Paolo Simioni","doi":"10.1016/j.bbcan.2025.189457","DOIUrl":"10.1016/j.bbcan.2025.189457","url":null,"abstract":"<div><div>Cholangiocarcinoma (CCA) is the liver malignancy with the most rapid increase in incidence and lethality in recent years. Venous thromboembolism (VTE) is a common complication of the cancer-associated hypercoagulable state, which may incite tumor progression and dissemination, thereby increasing cancer-related morbidity and mortality. Compared to other cancer types, occurrence of VTE in CCA has been underestimated, though recent evidence indicates it may behave as prognostic factor of worst outcome. Given the need for novel predictive scores and treatment approaches when VTE occurs, identifying subgroups of patients with CCA who would benefit from thromboprophylaxis without increasing the risk of bleeding is a crucial but still neglected aspect of the management. The aim of this review is to summarize current observations on the clinical significance, prediction, risk assessment and the underlying mechanisms of cancer-induced thrombogenesis in CCA, as well as to identify research areas ripe for prioritization in the near future.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189457"},"PeriodicalIF":9.7,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145132897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-18DOI: 10.1016/j.bbcan.2025.189455
Lasse von Bornemann Fløe , Maya Graham Pedersen , Bjarne K. Møller
Chimeric Antigen Receptor T (CAR-T) cell therapy is a promising new treatment category. Animal models have played a pivotal role in advancing CAR-T cell therapy. However, no animal model fully replicates human physiology, leading to unsuccessful translation from preclinical models to clinical trials. Understanding the advantages and limitations of various animal model choices requires insight into CAR-T cell mechanisms and their interactions across experimental contexts.
CAR-T cell immunobiology differs between animal models and humans. This disparity is reflected in the limited translational capacity of pharmacological parameters and the absence of key immunological interactions in animal models compared to those seen in human trials. Additionally, the antigen specificity of the CAR introduces translational limitations. Differences in antigen density and expression among different cellular populations across species are critical factors to consider when interpreting preclinical results. Xenoreactivity, stemming from the original T-cell receptor repertoire, also limits experimental duration and timing in mouse models.
Modeling human cancer in animal models requires many considerations. Cancer heterogeneity varies significantly between patient-derived xenografts and cell-line-based xenografts. Syngeneic models more accurately mimic interactions between CAR-T cells and other immune components, while xenograft models better reflect human tumor antigen expression. Beyond CAR-T-specific challenges, issues with standardization and replication in animal studies affect the reliability of the results. Furthermore, ethical guidelines should guide experimental planning to minimize animal use and prioritize humane treatment.
This review explores the strengths and limitations of animal models preclinical CAR-T cell therapy research, while offering critical considerations for interpreting results and designing experiments.
{"title":"Animal models in preclinical evaluation of CAR-T cell therapy: Advantages and limitations","authors":"Lasse von Bornemann Fløe , Maya Graham Pedersen , Bjarne K. Møller","doi":"10.1016/j.bbcan.2025.189455","DOIUrl":"10.1016/j.bbcan.2025.189455","url":null,"abstract":"<div><div>Chimeric Antigen Receptor T (CAR-T) cell therapy is a promising new treatment category. Animal models have played a pivotal role in advancing CAR-T cell therapy. However, no animal model fully replicates human physiology, leading to unsuccessful translation from preclinical models to clinical trials. Understanding the advantages and limitations of various animal model choices requires insight into CAR-T cell mechanisms and their interactions across experimental contexts.</div><div>CAR-T cell immunobiology differs between animal models and humans. This disparity is reflected in the limited translational capacity of pharmacological parameters and the absence of key immunological interactions in animal models compared to those seen in human trials. Additionally, the antigen specificity of the CAR introduces translational limitations. Differences in antigen density and expression among different cellular populations across species are critical factors to consider when interpreting preclinical results. Xenoreactivity, stemming from the original T-cell receptor repertoire, also limits experimental duration and timing in mouse models.</div><div>Modeling human cancer in animal models requires many considerations. Cancer heterogeneity varies significantly between patient-derived xenografts and cell-line-based xenografts. Syngeneic models more accurately mimic interactions between CAR-T cells and other immune components, while xenograft models better reflect human tumor antigen expression. Beyond CAR-T-specific challenges, issues with standardization and replication in animal studies affect the reliability of the results. Furthermore, ethical guidelines should guide experimental planning to minimize animal use and prioritize humane treatment.</div><div>This review explores the strengths and limitations of animal models preclinical CAR-T cell therapy research, while offering critical considerations for interpreting results and designing experiments.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189455"},"PeriodicalIF":9.7,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145103139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The process of mitochondrial fission is a major determinant of mitochondrial homeostasis. DRP1 is the chief architect of the mitochondrial fission process, and the DRP1 recruitment to the mitochondrial outer membrane is necessary for the mitochondrial division. DRP1 contributes to cancer progression by promoting cell proliferation, enhancing resistance to therapy, inhibiting apoptosis, suppressing immune responses, and sustaining cancer stem cell heterogeneity and self-renewal. Moreover, DRP1 drives metabolic reprogramming to support enhanced energy production and biosynthesis required for tumor growth and survival. In addition, DRP1-mediated mitochondrial fission also favours NLRP3 inflammasome activation within the tumor microenvironment, which regulates cancer progression. Interestingly, elevated levels of DRP1 expression have been identified as a significant prognostic marker, correlating with poor survival outcomes across multiple cancer types. Many DRP1 inhibitors have been developed for cancer treatment, but more specific and selective agents are needed to improve efficacy and reduce off-target effects. A comprehensive understanding of DRP1's role in cancer cells is essential for developing DRP1 inhibitors, which hold promise as novel anticancer therapies and may enhance the effectiveness of conventional treatments.
{"title":"Intricate role of DRP1 and associated mitochondrial fission signaling in carcinogenesis and cancer progression","authors":"Soumya Ranjan Mishra , Priyadarshini Mishra , Prakash Kumar Senapati , Kewal Kumar Mahapatra , Sujit Kumar Bhutia","doi":"10.1016/j.bbcan.2025.189453","DOIUrl":"10.1016/j.bbcan.2025.189453","url":null,"abstract":"<div><div>The process of mitochondrial fission is a major determinant of mitochondrial homeostasis. DRP1 is the chief architect of the mitochondrial fission process, and the DRP1 recruitment to the mitochondrial outer membrane is necessary for the mitochondrial division. DRP1 contributes to cancer progression by promoting cell proliferation, enhancing resistance to therapy, inhibiting apoptosis, suppressing immune responses, and sustaining cancer stem cell heterogeneity and self-renewal. Moreover, DRP1 drives metabolic reprogramming to support enhanced energy production and biosynthesis required for tumor growth and survival. In addition, DRP1-mediated mitochondrial fission also favours NLRP3 inflammasome activation within the tumor microenvironment, which regulates cancer progression. Interestingly, elevated levels of DRP1 expression have been identified as a significant prognostic marker, correlating with poor survival outcomes across multiple cancer types. Many DRP1 inhibitors have been developed for cancer treatment, but more specific and selective agents are needed to improve efficacy and reduce off-target effects. A comprehensive understanding of DRP1's role in cancer cells is essential for developing DRP1 inhibitors, which hold promise as novel anticancer therapies and may enhance the effectiveness of conventional treatments.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189453"},"PeriodicalIF":9.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145088253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-12DOI: 10.1016/j.bbcan.2025.189451
Sushmita Patra , Bishnu Prasad Behera , Birija Sankar Patro , Sujit Kumar Bhutia
As a cytoprotective mechanism, autophagy recycles damaged proteins and organelles via the lysosomal degradation pathway in response to diverse stress conditions. However, its role in tumor microenvironment, including oral cancer, is still a point of contention. Although excessive autophagy is associated with cell death, many studies have revealed elevated autophagy levels in advanced stages of oral cancer, providing a suitable niche for growth and proliferation. On the contrary, disruption of basal level autophagy also contributes to oral cancer development at the early stage due to increased oxidative stress and accumulation of genetic mutations. This atypical dependence of oral cancer cells on autophagy is associated with cellular features, stage, and requirements. The present study highlights the involvement of key autophagy-related proteins in oral cancer progression and explores their interaction with oncogenic signaling pathways that drive proliferation, chemoresistance, metabolic reprogramming, and metastasis. Furthermore, increased autophagy in cancer-associated fibroblasts, immune cells, and macrophages within the tumor microenvironment contributes to fibroblast activation, cytokine secretion, and immune suppression, enhancing tumor plasticity. Notably, crosstalk between autophagy and the NLRP3 inflammasome has emerged as a significant factor in promoting oral cancer progression and metastasis. Finally, accumulating evidence supports the therapeutic potential of autophagy modulators, which enhance apoptosis and suppress tumor growth, suggesting that targeting autophagy could offer promising treatment strategies for resistant oral cancers.
{"title":"Functional dichotomy of autophagy signaling in tumor microenvironment driving hallmarks in oral cancer","authors":"Sushmita Patra , Bishnu Prasad Behera , Birija Sankar Patro , Sujit Kumar Bhutia","doi":"10.1016/j.bbcan.2025.189451","DOIUrl":"10.1016/j.bbcan.2025.189451","url":null,"abstract":"<div><div>As a cytoprotective mechanism, autophagy recycles damaged proteins and organelles via the lysosomal degradation pathway in response to diverse stress conditions. However, its role in tumor microenvironment, including oral cancer, is still a point of contention. Although excessive autophagy is associated with cell death, many studies have revealed elevated autophagy levels in advanced stages of oral cancer, providing a suitable niche for growth and proliferation. On the contrary, disruption of basal level autophagy also contributes to oral cancer development at the early stage due to increased oxidative stress and accumulation of genetic mutations. This atypical dependence of oral cancer cells on autophagy is associated with cellular features, stage, and requirements. The present study highlights the involvement of key autophagy-related proteins in oral cancer progression and explores their interaction with oncogenic signaling pathways that drive proliferation, chemoresistance, metabolic reprogramming, and metastasis. Furthermore, increased autophagy in cancer-associated fibroblasts, immune cells, and macrophages within the tumor microenvironment contributes to fibroblast activation, cytokine secretion, and immune suppression, enhancing tumor plasticity. Notably, crosstalk between autophagy and the NLRP3 inflammasome has emerged as a significant factor in promoting oral cancer progression and metastasis. Finally, accumulating evidence supports the therapeutic potential of autophagy modulators, which enhance apoptosis and suppress tumor growth, suggesting that targeting autophagy could offer promising treatment strategies for resistant oral cancers.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189451"},"PeriodicalIF":9.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145066699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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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