Thymic epithelial cells (TEC) drive the proper differentiation of thymocytes for generating self-tolerant naïve T cells. TEC are functionally heterogeneous, as revealed by advancements in single-cell technologies, the development of new mouse models, and the examination of mouse, human, and zebrafish samples. While multiple cell-intrinsic regulators of TEC have been identified, many remain to be discovered. A comprehensive molecular characterization of each TEC subset and, ultimately, of all TECs, will help to develop strategies for their therapeutic modulation. Here, we review the potential role of the multifunctional transcription factor YY1 in thymus development and function, with a focus on TEC.
{"title":"The roles and perspectives of YY1 in immune central tolerance establishment","authors":"Gustavo Ulises Martínez-Ruiz , Ricardo Valle-Rios , Marco Velasco-Velazquez , Guillermo Aquino-Jarquin","doi":"10.1016/j.bbcan.2025.189469","DOIUrl":"10.1016/j.bbcan.2025.189469","url":null,"abstract":"<div><div>Thymic epithelial cells (TEC) drive the proper differentiation of thymocytes for generating self-tolerant naïve T cells. TEC are functionally heterogeneous, as revealed by advancements in single-cell technologies, the development of new mouse models, and the examination of mouse, human, and zebrafish samples. While multiple cell-intrinsic regulators of TEC have been identified, many remain to be discovered. A comprehensive molecular characterization of each TEC subset and, ultimately, of all TECs, will help to develop strategies for their therapeutic modulation. Here, we review the potential role of the multifunctional transcription factor YY1 in thymus development and function, with a focus on TEC.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189469"},"PeriodicalIF":9.7,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145254098","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 : 2025-10-03DOI: 10.1016/j.bbcan.2025.189468
Ana R. Gomes , Elisiário J. Tavares-da-Silva , Fernanda M.F. Roleira , Ana S. Pires
Pancreatic cancer remains one of the most life-threatening cancers worldwide with limited therapeutic options and a poor prognosis. Despite the advances in treatment regimens, the death rate of pancreatic cancer patients continues to rise, justifying the need for novel therapeutic agents. Steroidal derivatives, with their unique modifiable framework, have emerged as a promising class of compounds in drug discovery, namely for the search for novel anticancer drugs.
A comprehensive review of studies on the anticancer activity of synthetic and natural steroidal derivatives for potential pancreatic cancer treatment was conducted, highlighting their structural versatility, mechanisms of action, and recent advances in their development. For this, an extensive literature search was conducted in two main databases – PubMed and Web of Science.
In the preclinical setting, the steroidal derivatives described throughout this review display their cytotoxicity by different mechanisms, which culminate in cell death mostly by apoptosis. Remarkably, many of the pathways affected by this class of compounds are considered key players in many of the hallmarks of cancer, which reinforces the importance of studying steroidal derivatives for the treatment of pancreatic cancer.
This review summarises the current state of research and underscores the potential of steroidal derivatives as a groundwork for novel therapeutic approaches in pancreatic cancer management, outlining future directions for their development as effective anticancer agents.
胰腺癌仍然是世界上最危及生命的癌症之一，治疗选择有限，预后差。尽管治疗方案取得了进展，但胰腺癌患者的死亡率仍在继续上升，这证明需要新的治疗药物。甾体衍生物以其独特的可修饰框架，在药物发现，即寻找新的抗癌药物方面，已成为一类有前途的化合物。本文综述了合成甾体衍生物和天然甾体衍生物在胰腺癌治疗中的抗癌活性，重点介绍了它们的结构通用性、作用机制和最新进展。为此，在两个主要数据库PubMed和Web of Science中进行了广泛的文献检索。在临床前环境中，本综述中描述的甾体衍生物通过不同的机制显示其细胞毒性，其最终导致细胞凋亡。值得注意的是，受这类化合物影响的许多途径被认为是许多癌症特征的关键参与者，这加强了研究类固醇衍生物治疗胰腺癌的重要性。本文综述了甾体衍生物的研究现状，强调了其作为胰腺癌治疗新方法基础的潜力，并概述了其作为有效抗癌药物的未来发展方向。
{"title":"Steroidal derivatives in pancreatic cancer: Paving the way to new anticancer drugs","authors":"Ana R. Gomes , Elisiário J. Tavares-da-Silva , Fernanda M.F. Roleira , Ana S. Pires","doi":"10.1016/j.bbcan.2025.189468","DOIUrl":"10.1016/j.bbcan.2025.189468","url":null,"abstract":"<div><div>Pancreatic cancer remains one of the most life-threatening cancers worldwide with limited therapeutic options and a poor prognosis. Despite the advances in treatment regimens, the death rate of pancreatic cancer patients continues to rise, justifying the need for novel therapeutic agents. Steroidal derivatives, with their unique modifiable framework, have emerged as a promising class of compounds in drug discovery, namely for the search for novel anticancer drugs.</div><div>A comprehensive review of studies on the anticancer activity of synthetic and natural steroidal derivatives for potential pancreatic cancer treatment was conducted, highlighting their structural versatility, mechanisms of action, and recent advances in their development. For this, an extensive literature search was conducted in two main databases – PubMed and Web of Science.</div><div>In the preclinical setting, the steroidal derivatives described throughout this review display their cytotoxicity by different mechanisms, which culminate in cell death mostly by apoptosis. Remarkably, many of the pathways affected by this class of compounds are considered key players in many of the <em>hallmarks of cancer</em>, which reinforces the importance of studying steroidal derivatives for the treatment of pancreatic cancer.</div><div>This review summarises the current state of research and underscores the potential of steroidal derivatives as a groundwork for novel therapeutic approaches in pancreatic cancer management, outlining future directions for their development as effective anticancer agents.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189468"},"PeriodicalIF":9.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234472","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 : 2025-10-02DOI: 10.1016/j.bbcan.2025.189467
Hans Hendriks
Drug development remains a high-risk endeavour, particularly in oncology, where failure rates exceed 90 %. This review examines emerging tools and strategies designed to enhance preclinical success rates, aligning with the 3Rs principle: Reduction, Refinement, and Replacement of animal testing.
Traditional 2D in vitro screening remains fundamental in early anticancer drug development due to its cost-effectiveness and reproducibility. However, 3D in vitro culture systems, including patient-derived organoids, better recapitulate tumour structure, providing more accurate predictions of clinical response. Additionally, Organ-on-a-chip platforms further enhance physiological relevance and complement conventional animal toxicology models. Despite their promise, these technologies face challenges in standardisation, validation, and regulatory acceptance.
Artificial intelligence is also emerging as a transformative tool in oncology drug discovery and development. However, its widespread adoption is currently constrained by limited access to high-quality datasets, concerns around data security, privacy, and underdeveloped computational infrastructure.
For in vivo studies, patient-derived xenograft (PDX) models remain the gold standard, offering robust and translationally relevant platforms for efficacy testing. Hybrid models, such as PDX-derived organoids and PDX-derived cell cultures, provide complementary systems that integrate in vitro and in vivo insights.
While these innovations offer long-term potential to reduce animal use, more innovative experimental designs and methods, such as the Single Mouse Trial and the Hollow Fibre Assay, may reduce animal numbers in the short term without compromising data quality.
Together, these advances contribute to a more ethical, efficient, and predictive framework for the development of preclinical anticancer drugs.
{"title":"Advancing oncology drug development: Innovative approaches to enhance success rates while reducing animal testing","authors":"Hans Hendriks","doi":"10.1016/j.bbcan.2025.189467","DOIUrl":"10.1016/j.bbcan.2025.189467","url":null,"abstract":"<div><div>Drug development remains a high-risk endeavour, particularly in oncology, where failure rates exceed 90 %. This review examines emerging tools and strategies designed to enhance preclinical success rates, aligning with the 3Rs principle: Reduction, Refinement, and Replacement of animal testing.</div><div>Traditional 2D in vitro screening remains fundamental in early anticancer drug development due to its cost-effectiveness and reproducibility. However, 3D in vitro culture systems, including patient-derived organoids, better recapitulate tumour structure, providing more accurate predictions of clinical response. Additionally, Organ-on-a-chip platforms further enhance physiological relevance and complement conventional animal toxicology models. Despite their promise, these technologies face challenges in standardisation, validation, and regulatory acceptance.</div><div>Artificial intelligence is also emerging as a transformative tool in oncology drug discovery and development. However, its widespread adoption is currently constrained by limited access to high-quality datasets, concerns around data security, privacy, and underdeveloped computational infrastructure.</div><div>For in vivo studies, patient-derived xenograft (PDX) models remain the gold standard, offering robust and translationally relevant platforms for efficacy testing. Hybrid models, such as PDX-derived organoids and PDX-derived cell cultures, provide complementary systems that integrate in vitro and in vivo insights.</div><div>While these innovations offer long-term potential to reduce animal use, more innovative experimental designs and methods, such as the Single Mouse Trial and the Hollow Fibre Assay, may reduce animal numbers in the short term without compromising data quality.</div><div>Together, these advances contribute to a more ethical, efficient, and predictive framework for the development of preclinical anticancer drugs.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189467"},"PeriodicalIF":9.7,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145228412","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 signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that is essential in regulating cellular homeostasis. Aberrant and persistent activation of STAT3 triggers the oncogenic progression of multiple cancers. STAT3 can be activated by both canonical and non-canonical pathways, leading to its nuclear translocation and regulation of the transcription of multiple target genes to promote tumor cell proliferation, drug resistance, differentiation, inflammation, immune evasion, and angiogenesis. Persistent activation of STAT3 correlates with the poor prognosis of cancer patients. Notably, STAT3 plays a crucial role in the maintenance of cancer stem cells (CSCs), contributing to disease relapse, metastasis, and poor clinical outcomes. Given its multifaceted role in tumor biology, STAT3 is an attractive target for therapeutic intervention. Various small molecules, peptides, and natural compounds targeting STAT3 are currently under different stages of preclinical and clinical evaluation. Despite promising advances, challenges such as drug resistance, selectivity, and toxicity remain obstacles in the development of effective STAT3-targeted therapies. This review provides a comprehensive overview of STAT3 structure, activation mechanisms, and its functional role in tumor biology and CSC maintenance. We also highlight current progress in STAT3-targeted therapeutic strategies, including agents in clinical trials, and discuss the future potential of STAT3 inhibition in precision oncology.
{"title":"STAT3 axis in cancer and cancer stem cells: From oncogenesis to targeted therapies","authors":"Deepika Godugu, Rameswari Chilamakuri, Saurabh Agarwal","doi":"10.1016/j.bbcan.2025.189461","DOIUrl":"10.1016/j.bbcan.2025.189461","url":null,"abstract":"<div><div>The signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that is essential in regulating cellular homeostasis. Aberrant and persistent activation of STAT3 triggers the oncogenic progression of multiple cancers. STAT3 can be activated by both canonical and non-canonical pathways, leading to its nuclear translocation and regulation of the transcription of multiple target genes to promote tumor cell proliferation, drug resistance, differentiation, inflammation, immune evasion, and angiogenesis. Persistent activation of STAT3 correlates with the poor prognosis of cancer patients. Notably, STAT3 plays a crucial role in the maintenance of cancer stem cells (CSCs), contributing to disease relapse, metastasis, and poor clinical outcomes. Given its multifaceted role in tumor biology, STAT3 is an attractive target for therapeutic intervention. Various small molecules, peptides, and natural compounds targeting STAT3 are currently under different stages of preclinical and clinical evaluation. Despite promising advances, challenges such as drug resistance, selectivity, and toxicity remain obstacles in the development of effective STAT3-targeted therapies. This review provides a comprehensive overview of STAT3 structure, activation mechanisms, and its functional role in tumor biology and CSC maintenance. We also highlight current progress in STAT3-targeted therapeutic strategies, including agents in clinical trials, and discuss the future potential of STAT3 inhibition in precision oncology.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189461"},"PeriodicalIF":9.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208669","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 : 2025-09-26DOI: 10.1016/j.bbcan.2025.189465
Yiqing Zhang , Jianxin Lyu , Hezhi Fang
Cancer cells often survive in harsh microenvironments. To sustain rapid growth and proliferation, they reprogram metabolic pathways through multiple mechanisms to meet the demands of biosynthesis and energy production. Both essential and non-essential amino acids support cancer cell synthesis of macromolecules such as proteins and nucleotides. They also participate in diverse biological processes, including oxidative stress defense, epigenetic regulation, and signaling pathway modulation. In this review, we summarize the role of amino acid metabolism in cancer initiation and progression, and highlight recent advances in therapies targeting amino acid metabolism. The aim of this review is to stimulate both basic research and translational studies on cancer therapy through targeting amino acid metabolism.
{"title":"Rewiring amino acids in cancer","authors":"Yiqing Zhang , Jianxin Lyu , Hezhi Fang","doi":"10.1016/j.bbcan.2025.189465","DOIUrl":"10.1016/j.bbcan.2025.189465","url":null,"abstract":"<div><div>Cancer cells often survive in harsh microenvironments. To sustain rapid growth and proliferation, they reprogram metabolic pathways through multiple mechanisms to meet the demands of biosynthesis and energy production. Both essential and non-essential amino acids support cancer cell synthesis of macromolecules such as proteins and nucleotides. They also participate in diverse biological processes, including oxidative stress defense, epigenetic regulation, and signaling pathway modulation. In this review, we summarize the role of amino acid metabolism in cancer initiation and progression, and highlight recent advances in therapies targeting amino acid metabolism. The aim of this review is to stimulate both basic research and translational studies on cancer therapy through targeting amino acid metabolism.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189465"},"PeriodicalIF":9.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187924","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 : 2025-09-26DOI: 10.1016/j.bbcan.2025.189466
Puja Kumari , Sagarika Dash , Dibyendu Samanta
Tumorigenesis is a complex, multifaceted process that deregulates normal cellular functions, including cell growth, proliferation, and apoptosis. The primary factors driving tumorigenesis include the activation of oncogenes, inhibition of tumor suppressor genes, and the disruption of cell-cell contact. E-cadherin, a critical component of adherens junctions, plays an integral role in cell adhesion, maintaining tissue integrity, and contributing to developmental processes. E-cadherin facilitates the regulation of proliferation through contact inhibition under physiological conditions, acting as a tumor suppressor, and the alterations in E-cadherin expression are a major driving force in the development of various cancers. However, ongoing research has revealed the significance of E-cadherin in cancer progression, emphasizing its functional duality in tumorigenesis. This review summarizes E-cadherin's diverse and complex functions in various cancers, the underlying molecular mechanisms, and its role as a potential cancer biomarker across different cancer types. Further, we highlight numerous therapeutic strategies designed to target E-cadherin expression to treat various cancers.
{"title":"E-cadherin: A potential biomarker in cancer and a therapeutic target","authors":"Puja Kumari , Sagarika Dash , Dibyendu Samanta","doi":"10.1016/j.bbcan.2025.189466","DOIUrl":"10.1016/j.bbcan.2025.189466","url":null,"abstract":"<div><div>Tumorigenesis is a complex, multifaceted process that deregulates normal cellular functions, including cell growth, proliferation, and apoptosis. The primary factors driving tumorigenesis include the activation of oncogenes, inhibition of tumor suppressor genes, and the disruption of cell-cell contact. E-cadherin, a critical component of adherens junctions, plays an integral role in cell adhesion, maintaining tissue integrity, and contributing to developmental processes. E-cadherin facilitates the regulation of proliferation through contact inhibition under physiological conditions, acting as a tumor suppressor, and the alterations in E-cadherin expression are a major driving force in the development of various cancers. However, ongoing research has revealed the significance of E-cadherin in cancer progression, emphasizing its functional duality in tumorigenesis. This review summarizes E-cadherin's diverse and complex functions in various cancers, the underlying molecular mechanisms, and its role as a potential cancer biomarker across different cancer types. Further, we highlight numerous therapeutic strategies designed to target E-cadherin expression to treat various cancers.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189466"},"PeriodicalIF":9.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187957","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 : 2025-09-26DOI: 10.1016/j.bbcan.2025.189463
Hongdan Chen , Yinde Huang , Supeng Yin , Chong Li , Fan Zhang
Tumor mechanical alterations have emerged as a critical but underexplored marker of cancer. Cells within the tumor microenvironment (TME) are constantly exposed to matrix remodeling, aberrant shear stress, cytoskeletal tension, and tumor thrombi, all of which modulate tumor progression, therapy resistance, and stromal remodeling. This review summarizes recent advances in understanding how mechanical cues regulate tumor behavior through mechanotransduction pathways, and evaluates therapeutic strategies targeting extracellular matrix (ECM) stiffness, cytoskeletal contractility, ion channels, and physical interventions. While these approaches demonstrate translational promise, most studies remain descriptive, and major challenges, including off-target effects, limited drug penetration, and biomarker validation, continue to impede clinical application. We highlight the emerging concept of “tumor mechanomics”, which integrates biomechanical fingerprints with molecular and clinical data, offering a framework for developing predictive biomarkers and guiding precision oncology.
{"title":"The mechanical landscape of cancer: Exploring mechanical characteristics-based therapeutic approaches","authors":"Hongdan Chen , Yinde Huang , Supeng Yin , Chong Li , Fan Zhang","doi":"10.1016/j.bbcan.2025.189463","DOIUrl":"10.1016/j.bbcan.2025.189463","url":null,"abstract":"<div><div>Tumor mechanical alterations have emerged as a critical but underexplored marker of cancer. Cells within the tumor microenvironment (TME) are constantly exposed to matrix remodeling, aberrant shear stress, cytoskeletal tension, and tumor thrombi, all of which modulate tumor progression, therapy resistance, and stromal remodeling. This review summarizes recent advances in understanding how mechanical cues regulate tumor behavior through mechanotransduction pathways, and evaluates therapeutic strategies targeting extracellular matrix (ECM) stiffness, cytoskeletal contractility, ion channels, and physical interventions. While these approaches demonstrate translational promise, most studies remain descriptive, and major challenges, including off-target effects, limited drug penetration, and biomarker validation, continue to impede clinical application. We highlight the emerging concept of “tumor mechanomics”, which integrates biomechanical fingerprints with molecular and clinical data, offering a framework for developing predictive biomarkers and guiding precision oncology.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189463"},"PeriodicalIF":9.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187980","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 : 2025-09-26DOI: 10.1016/j.bbcan.2025.189464
Ying Wang , Zhixin Ye , Ye Yuan , Chuanhao Wang , Gang Chen , Yonghui Zhang
Emerging evidence in cancer neuroscience highlights the crucial role of sensory nerves in tumor progression, an aspect of cancer pathobiology previously overlooked. Mechanistically, tumor-associated sensory neurons establish a self-reinforcing oncogenic loop via secreted neurotrophic factors (e.g., NGF/BDNF), which directly promote cancer cell growth, spread, and treatment resistance through Trk activation. Concurrently, tumors rewire their local environment through dysregulated expression of axon guidance molecules, facilitating invasive growth. Importantly, nociceptive signaling activated during perineural invasion not only mediates cancer-related pain but also shapes an immunosuppressive microenvironment through neuropeptide-mediated changes in immune cell function. Current therapeutic strategies targeting tumor-associated nerves focus on: (1) Pharmacological blockade of nerve-tumor communication using small-molecule inhibitors (e.g., Trk inhibitor larotrectinib); (2) Bioelectronic modulation of neural activity via modalities such as transcutaneous electrical nerve stimulation. Notably, preclinical models reveal enhanced efficacy when combining neural modulation with immune checkpoint inhibitors. Technological breakthroughs, including single-cell analysis for precise nerve targeting and advanced drug delivery systems, are improving therapeutic precision. Consequently, understanding the complex interactions between nerves and tumors requires integrated approaches combining cancer biology, neuroimmunology, and systems neuroscience. This conceptual shift not only reshapes our understanding of cancer pathophysiology but also opens new avenues for precision therapies aligned with modern oncology.
{"title":"Sensory neuro-tumor crosstalk: Therapeutic opportunities and emerging frontiers in cancer neuroscience","authors":"Ying Wang , Zhixin Ye , Ye Yuan , Chuanhao Wang , Gang Chen , Yonghui Zhang","doi":"10.1016/j.bbcan.2025.189464","DOIUrl":"10.1016/j.bbcan.2025.189464","url":null,"abstract":"<div><div>Emerging evidence in cancer neuroscience highlights the crucial role of sensory nerves in tumor progression, an aspect of cancer pathobiology previously overlooked. Mechanistically, tumor-associated sensory neurons establish a self-reinforcing oncogenic loop via secreted neurotrophic factors (e.g., NGF/BDNF), which directly promote cancer cell growth, spread, and treatment resistance through Trk activation. Concurrently, tumors rewire their local environment through dysregulated expression of axon guidance molecules, facilitating invasive growth. Importantly, nociceptive signaling activated during perineural invasion not only mediates cancer-related pain but also shapes an immunosuppressive microenvironment through neuropeptide-mediated changes in immune cell function. Current therapeutic strategies targeting tumor-associated nerves focus on: (1) Pharmacological blockade of nerve-tumor communication using small-molecule inhibitors (e.g., Trk inhibitor larotrectinib); (2) Bioelectronic modulation of neural activity via modalities such as transcutaneous electrical nerve stimulation. Notably, preclinical models reveal enhanced efficacy when combining neural modulation with immune checkpoint inhibitors. Technological breakthroughs, including single-cell analysis for precise nerve targeting and advanced drug delivery systems, are improving therapeutic precision. Consequently, understanding the complex interactions between nerves and tumors requires integrated approaches combining cancer biology, neuroimmunology, and systems neuroscience. This conceptual shift not only reshapes our understanding of cancer pathophysiology but also opens new avenues for precision therapies aligned with modern oncology.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189464"},"PeriodicalIF":9.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187971","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.2025.189460
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.
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