Pub Date : 2025-07-21DOI: 10.1016/j.semcancer.2025.07.009
Yayu Chen , Zhishuang Ye , Rong-Quan He , Gang Chen , Daniel Xin Zhang
Non-coding RNAs (ncRNAs) are increasingly recognized as crucial regulators in the pathophysiology of cancer treatment–induced cardiovascular toxicity, which largely stems from their capacity to orchestrate a wide range of gene expression networks. Emerging evidence has uncovered complex and critical functions of ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, in mediating cardiotoxicity during cancer treatment. Here, we revisit the mechanisms of major anti-cancer treatment modalities and detail how they may lead to cardiovascular toxicity, which involves a myriad of key, interconnected processes, such as apoptosis, DNA damage, oxidative stress, mitochondrial damage, and autophagy. We further underscore the pivotal roles of ncRNAs within the cardio-oncology landscape mechanistically and analyze their clinical potentials to predict, detect, and treat cardiovascular damage in oncology settings. With this review, we aim to provide a comprehensive and up-to-date landscape of ncRNAs in the rapidly revolving field of cancer treatment–related cardiovascular toxicity, highlighting how such fundamental discoveries may guide future clinical applications.
{"title":"Landscape of non-coding RNAs in cancer treatment-induced cardiovascular toxicity: From mechanistic insights to clinical implications","authors":"Yayu Chen , Zhishuang Ye , Rong-Quan He , Gang Chen , Daniel Xin Zhang","doi":"10.1016/j.semcancer.2025.07.009","DOIUrl":"10.1016/j.semcancer.2025.07.009","url":null,"abstract":"<div><div>Non-coding RNAs (ncRNAs) are increasingly recognized as crucial regulators in the pathophysiology of cancer treatment–induced cardiovascular toxicity, which largely stems from their capacity to orchestrate a wide range of gene expression networks. Emerging evidence has uncovered complex and critical functions of ncRNAs, including microRNAs, long non-coding RNAs, and circular RNAs, in mediating cardiotoxicity during cancer treatment. Here, we revisit the mechanisms of major anti-cancer treatment modalities and detail how they may lead to cardiovascular toxicity, which involves a myriad of key, interconnected processes, such as apoptosis, DNA damage, oxidative stress, mitochondrial damage, and autophagy. We further underscore the pivotal roles of ncRNAs within the cardio-oncology landscape mechanistically and analyze their clinical potentials to predict, detect, and treat cardiovascular damage in oncology settings. With this review, we aim to provide a comprehensive and up-to-date landscape of ncRNAs in the rapidly revolving field of cancer treatment–related cardiovascular toxicity, highlighting how such fundamental discoveries may guide future clinical applications.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"115 ","pages":"Pages 16-39"},"PeriodicalIF":15.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699379","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 : 2025-07-21DOI: 10.1016/j.semcancer.2025.07.008
Adriana Albini , Anna Rita Cantelmo , Lorenzo Mortara , Douglas M. Noonan , Giovanni Corso
Obesity and type 2 diabetes are major risk factors for cardiovascular diseases and multiple malignancies, and epidemiology reveals an increasing burden of obesity-related cancers, in particular liver, pancreatic and endometrial. Obesity is also clearly associated with an increased risk of breast cancer, particularly in postmenopausal women. Chronic hyperinsulinemia, systemic inflammation, and metabolic dysregulation create a tumor-promoting environment, emphasizing the need for interventions that target metabolic health and can provide cancer prevention or interception. This review examines the potential cancer-preventive effects of antidiabetic and anti-obesity drugs, summarizing current preclinical and clinical evidence on their mechanisms and efficacy. Among these agents, metformin has been extensively studied, demonstrating anticancer properties through AMP-activated protein kinase activation, mammalian target of rapamycin inhibition, and reduced insulin-like growth factor 1 signaling. Glucagon-like peptide-1 receptor agonists, including semaglutide and tirzepatide, promote weight loss, insulin sensitivity, and anti-inflammatory effects, with emerging evidence suggesting direct tumor-suppressive actions. Sodium-glucose cotransporter 2 inhibitors modulate tumor metabolism by reducing glucose availability and mitigating systemic inflammation. Other agents, including dipeptidyl peptidase-4 inhibitors, thiazolidinediones, sulfonylureas, and alpha-glucosidase inhibitors, have shown mixed evidence regarding their potential anticancer effects, necessitating further investigation. While observational studies and meta-analyses suggest a potential reduction in cancer risk with certain antidiabetic and anti-obesity agents, randomized controlled trials specifically assessing cancer prevention are limited. Additionally, long-term safety concerns, including potential tumor-promoting effects in specific contexts, warrant further investigation. Future research should focus on large-scale clinical trials and mechanistic studies to validate the oncologic benefits and risks of these agents.
{"title":"Cancer prevention and interception with antidiabetic and anti-obesity drugs: Current and future perspectives","authors":"Adriana Albini , Anna Rita Cantelmo , Lorenzo Mortara , Douglas M. Noonan , Giovanni Corso","doi":"10.1016/j.semcancer.2025.07.008","DOIUrl":"10.1016/j.semcancer.2025.07.008","url":null,"abstract":"<div><div>Obesity and type 2 diabetes are major risk factors for cardiovascular diseases and multiple malignancies, and epidemiology reveals an increasing burden of obesity-related cancers, in particular liver, pancreatic and endometrial. Obesity is also clearly associated with an increased risk of breast cancer, particularly in postmenopausal women. Chronic hyperinsulinemia, systemic inflammation, and metabolic dysregulation create a tumor-promoting environment, emphasizing the need for interventions that target metabolic health and can provide cancer prevention or interception. This review examines the potential cancer-preventive effects of antidiabetic and anti-obesity drugs, summarizing current preclinical and clinical evidence on their mechanisms and efficacy. Among these agents, metformin has been extensively studied, demonstrating anticancer properties through AMP-activated protein kinase activation, mammalian target of rapamycin inhibition, and reduced insulin-like growth factor 1 signaling. Glucagon-like peptide-1 receptor agonists, including semaglutide and tirzepatide, promote weight loss, insulin sensitivity, and anti-inflammatory effects, with emerging evidence suggesting direct tumor-suppressive actions. Sodium-glucose cotransporter 2 inhibitors modulate tumor metabolism by reducing glucose availability and mitigating systemic inflammation. Other agents, including dipeptidyl peptidase-4 inhibitors, thiazolidinediones, sulfonylureas, and alpha-glucosidase inhibitors, have shown mixed evidence regarding their potential anticancer effects, necessitating further investigation. While observational studies and meta-analyses suggest a potential reduction in cancer risk with certain antidiabetic and anti-obesity agents, randomized controlled trials specifically assessing cancer prevention are limited. Additionally, long-term safety concerns, including potential tumor-promoting effects in specific contexts, warrant further investigation. Future research should focus on large-scale clinical trials and mechanistic studies to validate the oncologic benefits and risks of these agents.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"115 ","pages":"Pages 40-52"},"PeriodicalIF":15.7,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144699378","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 : 2025-07-08DOI: 10.1016/j.semcancer.2025.07.002
Bahadır Köylü , Cem Sulu , Volkan Demirhan Yumuk , Perran Fulden Yumuk
Sarcopenic obesity is a distinct clinical condition characterized by the coexistence of excess fat and reduced muscle mass. Although the prevalence of sarcopenic obesity varies depending on the definition used, it is increasingly recognized as a significant health concern, regardless of age and underlying disease. Despite limited understanding of the crosstalk between sarcopenic obesity and cancer, emerging evidence suggests that sarcopenic obesity not only promotes a metabolic and inflammatory environment conducive to cancer progression but also profoundly impacts treatment efficacy, safety, and survival outcomes. This review provides a concise overview of the key aspects of sarcopenic obesity, with a particular focus on its role in the cancer setting. We also assess existing evidence on its influence on oncological outcomes in both early and advanced stages of the various solid tumor types.
{"title":"The impact of sarcopenic obesity on cancer clinical outcomes","authors":"Bahadır Köylü , Cem Sulu , Volkan Demirhan Yumuk , Perran Fulden Yumuk","doi":"10.1016/j.semcancer.2025.07.002","DOIUrl":"10.1016/j.semcancer.2025.07.002","url":null,"abstract":"<div><div>Sarcopenic obesity is a distinct clinical condition characterized by the coexistence of excess fat and reduced muscle mass. Although the prevalence of sarcopenic obesity varies depending on the definition used, it is increasingly recognized as a significant health concern, regardless of age and underlying disease. Despite limited understanding of the crosstalk between sarcopenic obesity and cancer, emerging evidence suggests that sarcopenic obesity not only promotes a metabolic and inflammatory environment conducive to cancer progression but also profoundly impacts treatment efficacy, safety, and survival outcomes. This review provides a concise overview of the key aspects of sarcopenic obesity, with a particular focus on its role in the cancer setting. We also assess existing evidence on its influence on oncological outcomes in both early and advanced stages of the various solid tumor types.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"114 ","pages":"Pages 203-214"},"PeriodicalIF":12.1,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588547","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 : 2025-07-07DOI: 10.1016/j.semcancer.2025.06.011
Aman Wang, Jiwei Liu
Cardio-oncology is an emerging interdisciplinary field focused on the intersection of cancer and cardiovascular disease. With the rising incidence of both cancer and cardiovascular disease in China, establishing a strong cardio-oncology framework has become essential. This review examines the historical development, clinical practices, and key milestones of cardio-oncology in China, emphasizing the importance of multidisciplinary teams, specialized guidelines, and international collaborations. Additionally, it discusses the current challenges and future opportunities for advancing cardio-oncology within China’s healthcare landscape.
{"title":"From awareness to action: Revolutionizing cardio-oncology in China","authors":"Aman Wang, Jiwei Liu","doi":"10.1016/j.semcancer.2025.06.011","DOIUrl":"10.1016/j.semcancer.2025.06.011","url":null,"abstract":"<div><div>Cardio-oncology is an emerging interdisciplinary field focused on the intersection of cancer and cardiovascular disease. With the rising incidence of both cancer and cardiovascular disease in China, establishing a strong cardio-oncology framework has become essential. This review examines the historical development, clinical practices, and key milestones of cardio-oncology in China, emphasizing the importance of multidisciplinary teams, specialized guidelines, and international collaborations. Additionally, it discusses the current challenges and future opportunities for advancing cardio-oncology within China’s healthcare landscape.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"114 ","pages":"Pages 195-202"},"PeriodicalIF":12.1,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144588546","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 : 2025-07-05DOI: 10.1016/j.semcancer.2025.07.001
Maria Isabela Bloise Alves Caldas Sawada , Monique de Fatima de Mello Santana , Milena Gomes Vancini , Marisa Passarelli
Plasma lipid and lipoprotein profiles are recognized as key modulators in breast cancer (BC) development. Notably, the association between high-density lipoprotein cholesterol (HDLc) and BC remains controversial, with studies reporting positive, negative, or no correlation. This inconsistency may arise from the clinical metrics used to quantify high-density lipoproteins (HDL), such as HDLc and apolipoprotein (apo) A-1, which may not accurately reflect HDL functionality in modulating the tumor microenvironment. Moreover, HDL particles isolated from plasma may undergo modifications influenced by tumor activity, varying with disease stage, severity, and treatment. In this review, we are critically reopening Pandora´s box analyzing evidence on HDLc plasma levels and HDL functionality in BC. Specifically, HDL contributes to tumor regulation by removing excess cellular cholesterol, thereby limiting sterol availability for cell replication and metastasis. Additionally, HDL exerts antioxidant and anti-inflammatory effects and acts as a carrier of bioactive proteins, lipids, and microRNAs, facilitating their delivery to target cells and modulating intracellular signaling and gene expression. Collectively, HDL functionality may serve as a predictor of therapeutic response and clinical outcomes in BC.
{"title":"Reopening Pandora’s box: Is there a role for HDL in breast cancer?","authors":"Maria Isabela Bloise Alves Caldas Sawada , Monique de Fatima de Mello Santana , Milena Gomes Vancini , Marisa Passarelli","doi":"10.1016/j.semcancer.2025.07.001","DOIUrl":"10.1016/j.semcancer.2025.07.001","url":null,"abstract":"<div><div>Plasma lipid and lipoprotein profiles are recognized as key modulators in breast cancer (BC) development. Notably, the association between high-density lipoprotein cholesterol (HDLc) and BC remains controversial, with studies reporting positive, negative, or no correlation. This inconsistency may arise from the clinical metrics used to quantify high-density lipoproteins (HDL), such as HDLc and apolipoprotein (apo) A-1, which may not accurately reflect HDL functionality in modulating the tumor microenvironment. Moreover, HDL particles isolated from plasma may undergo modifications influenced by tumor activity, varying with disease stage, severity, and treatment. In this review, we are critically reopening Pandora´s box analyzing evidence on HDLc plasma levels and HDL functionality in BC. Specifically, HDL contributes to tumor regulation by removing excess cellular cholesterol, thereby limiting sterol availability for cell replication and metastasis. Additionally, HDL exerts antioxidant and anti-inflammatory effects and acts as a carrier of bioactive proteins, lipids, and microRNAs, facilitating their delivery to target cells and modulating intracellular signaling and gene expression. Collectively, HDL functionality may serve as a predictor of therapeutic response and clinical outcomes in BC.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"114 ","pages":"Pages 227-241"},"PeriodicalIF":12.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584724","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 : 2025-07-01Epub Date: 2025-03-07DOI: 10.1016/j.semcancer.2025.02.013
Wenzheng Guo, Zhibing Duan, Jingjing Wu, Binhua P. Zhou
Epithelial-mesenchymal transition (EMT) is a cellular de-differentiation process that provides cells with the increased plasticity and stem cell-like traits required during embryonic development, tissue remodeling, wound healing and metastasis. Morphologically, EMT confers tumor cells with fibroblast-like properties that lead to the rearrangement of cytoskeleton (loss of stiffness) and decrease of membrane rigidity by incorporating high level of poly-unsaturated fatty acids (PUFA) in their phospholipid membrane. Although large amounts of PUFA in membrane reduces rigidity and offers capabilities for tumor cells with the unbridled ability to stretch, bend and twist in metastasis, these PUFA are highly susceptible to lipid peroxidation, which leads to the breakdown of membrane integrity and, ultimately results in ferroptosis. To escape the ferroptotic risk, EMT also triggers the rewiring of metabolic program, particularly in lipid metabolism, to enforce the epigenetic regulation of EMT and mitigate the potential damages from ferroptosis. Thus, the interplay among EMT, lipid metabolism, and ferroptosis highlights a new layer of intricated regulation in cancer biology and metastasis. Here we summarize the latest findings and discuss these mutual interactions. Finally, we provide perspectives of how these interplays contribute to cellular plasticity and ferroptosis resistance in metastatic tumor cells that can be explored for innovative therapeutic interventions.
{"title":"Epithelial-mesenchymal transition promotes metabolic reprogramming to suppress ferroptosis","authors":"Wenzheng Guo, Zhibing Duan, Jingjing Wu, Binhua P. Zhou","doi":"10.1016/j.semcancer.2025.02.013","DOIUrl":"10.1016/j.semcancer.2025.02.013","url":null,"abstract":"<div><div>Epithelial-mesenchymal transition (EMT) is a cellular de-differentiation process that provides cells with the increased plasticity and stem cell-like traits required during embryonic development, tissue remodeling, wound healing and metastasis. Morphologically, EMT confers tumor cells with fibroblast-like properties that lead to the rearrangement of cytoskeleton (loss of stiffness) and decrease of membrane rigidity by incorporating high level of poly-unsaturated fatty acids (PUFA) in their phospholipid membrane. Although large amounts of PUFA in membrane reduces rigidity and offers capabilities for tumor cells with the unbridled ability to stretch, bend and twist in metastasis, these PUFA are highly susceptible to lipid peroxidation, which leads to the breakdown of membrane integrity and, ultimately results in ferroptosis. To escape the ferroptotic risk, EMT also triggers the rewiring of metabolic program, particularly in lipid metabolism, to enforce the epigenetic regulation of EMT and mitigate the potential damages from ferroptosis. Thus, the interplay among EMT, lipid metabolism, and ferroptosis highlights a new layer of intricated regulation in cancer biology and metastasis. Here we summarize the latest findings and discuss these mutual interactions. Finally, we provide perspectives of how these interplays contribute to cellular plasticity and ferroptosis resistance in metastatic tumor cells that can be explored for innovative therapeutic interventions.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 20-35"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586697","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}
Obesity induces systemic perturbations of tissue homeostasis, leading to dyslipidemia, insulin resistance and chronic state of inflammation. Evidence from clinical and preclinical studies links excess of adiposity with increased cancer incidence and suggests that chronic inflammation may contribute to increased cancer risk in obese patients. Over the last decades of obesity research, multifaced and complicated effects of abnormal or excessive expansion of Adipose Tissue have been uncovered. In particular, it is widely described how obesity can exacerbate the tumorigenesis for instance by fueling soluble signals and adipokines and by enhancing tissue inflammation and altering the hormonal balance. Less is known about the paracrine effects of the cancer-associated adipocytes on the tumor cells and still poorly explored is the reciprocal communication between cancer cells and the adipose component of the tumor microenvironment (TME). In this review, we will address the mechanisms by which the peritumoral Adipose Tissue can influence the dynamics of tumoral cells. We will discuss how obesity-induced changes in the tumor microenvironment may enhance tumor growth and aggressive characteristics leading to increased invasiveness and metastatic progression of cancer that leads to a worsen cancer survival in obese subjects. We conclude that targeting the peritumoral adipose component of the TME would be a therapeutic option to prevent cancer development.
{"title":"The impact of the tumor microenvironment in the dual burden of obesity-cancer link","authors":"Serena Sagliocchi , Lucia Acampora , Biagio Barone , Felice Crocetto , Monica Dentice","doi":"10.1016/j.semcancer.2025.03.001","DOIUrl":"10.1016/j.semcancer.2025.03.001","url":null,"abstract":"<div><div>Obesity induces systemic perturbations of tissue homeostasis, leading to dyslipidemia, insulin resistance and chronic state of inflammation. Evidence from clinical and preclinical studies links excess of adiposity with increased cancer incidence and suggests that chronic inflammation may contribute to increased cancer risk in obese patients. Over the last decades of obesity research, multifaced and complicated effects of abnormal or excessive expansion of Adipose Tissue have been uncovered. In particular, it is widely described how obesity can exacerbate the tumorigenesis for instance by fueling soluble signals and adipokines and by enhancing tissue inflammation and altering the hormonal balance. Less is known about the paracrine effects of the cancer-associated adipocytes on the tumor cells and still poorly explored is the reciprocal communication between cancer cells and the adipose component of the tumor microenvironment (TME). In this review, we will address the mechanisms by which the peritumoral Adipose Tissue can influence the dynamics of tumoral cells. We will discuss how obesity-induced changes in the tumor microenvironment may enhance tumor growth and aggressive characteristics leading to increased invasiveness and metastatic progression of cancer that leads to a worsen cancer survival in obese subjects. We conclude that targeting the peritumoral adipose component of the TME would be a therapeutic option to prevent cancer development.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 36-42"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701202","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 : 2025-07-01Epub Date: 2025-04-12DOI: 10.1016/j.semcancer.2025.04.001
Yuki Fujii , Zahra Asadi , Kamiya Mehla
Cathepsins, a group of lysosomal peptidases, have traditionally been recognized as tumor facilitators. Recent research, however, highlights their critical role in orchestrating cancer and the tumor microenvironment (TME). Primality, cathepsins degrade extracellular matrix, enabling cancer cells to invade and metastasize, while also promoting vascular endothelial infiltration and subsequent angiogenesis. Additionally, cathepsins boost fibroblast growth, thereby supporting tumor progression. More importantly, cathepsins are pivotal in modulating immune cells within the TME by regulating their recruitment, antigen processing and presentation, differentiation, and cell death, primarily contributing to immune suppression. Given their overexpression in tumors and elevated levels in the circulation of cancer patients, it is crucial to consider the systemic effects of cathepsins. Although the comprehensive role of cathepsins in cancer patients’ bodies remains underexplored, they likely influence systemic immunity and inflammation, cellular metabolism, muscle wasting, and distant metastasis through their unique proteolytic functions. Notably, cathepsins also confer resistance to chemoradiotherapy by rewriting the cellular profile within the TME. In this context, promising results are emerging from studies combining cathepsin inhibitors with conventional therapies to suppress tumor development effectively. This review aims to decipher the cathepsin-driven networks within cancer cells and the TME, detailing their contribution to chemoradioresistance by reshaping both micro- and macroenvironments. Furthermore, we explore current and future perspectives on therapies targeting cathepsins’ interactions, offering insights into innovative treatment strategies.
{"title":"Cathepsins: Emerging targets in the tumor ecosystem to overcome cancers","authors":"Yuki Fujii , Zahra Asadi , Kamiya Mehla","doi":"10.1016/j.semcancer.2025.04.001","DOIUrl":"10.1016/j.semcancer.2025.04.001","url":null,"abstract":"<div><div>Cathepsins, a group of lysosomal peptidases, have traditionally been recognized as tumor facilitators. Recent research, however, highlights their critical role in orchestrating cancer and the tumor microenvironment (TME). Primality, cathepsins degrade extracellular matrix, enabling cancer cells to invade and metastasize, while also promoting vascular endothelial infiltration and subsequent angiogenesis. Additionally, cathepsins boost fibroblast growth, thereby supporting tumor progression. More importantly, cathepsins are pivotal in modulating immune cells within the TME by regulating their recruitment, antigen processing and presentation, differentiation, and cell death, primarily contributing to immune suppression. Given their overexpression in tumors and elevated levels in the circulation of cancer patients, it is crucial to consider the systemic effects of cathepsins. Although the comprehensive role of cathepsins in cancer patients’ bodies remains underexplored, they likely influence systemic immunity and inflammation, cellular metabolism, muscle wasting, and distant metastasis through their unique proteolytic functions. Notably, cathepsins also confer resistance to chemoradiotherapy by rewriting the cellular profile within the TME. In this context, promising results are emerging from studies combining cathepsin inhibitors with conventional therapies to suppress tumor development effectively. This review aims to decipher the cathepsin-driven networks within cancer cells and the TME, detailing their contribution to chemoradioresistance by reshaping both micro- and macroenvironments. Furthermore, we explore current and future perspectives on therapies targeting cathepsins’ interactions, offering insights into innovative treatment strategies.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"112 ","pages":"Pages 150-166"},"PeriodicalIF":12.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143870470","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 : 2025-06-26DOI: 10.1016/j.semcancer.2025.06.010
Gerardo Sarno , Claudia Reytor-González , Evelyn Frias-Toral , Martín Campuzano-Donoso , Christos S. Katsanos , Daniel Simancas-Racines
Obesity significantly affects gastrointestinal cancer surgery outcomes by creating complex challenges throughout the preoperative, intraoperative, and postoperative stages. This narrative review explores the intricate relationship between obesity and GIC surgery, highlighting the dual burden of obesity as a global public health issue and a determinant of surgical complications. The review aims to analyze physiological and technical hurdles, including limited visibility, prolonged operative times, increased perioperative risks, and adverse recovery outcomes associated with obesity. Evidence emphasizes the critical role of excess visceral fat, systemic inflammation, and insulin resistance in elevating surgical risks. Mitigation strategies involve preoperative nutritional optimization, use of advanced surgical technologies such as robotic-assisted and laparoscopic systems, and individualized postoperative care, encompassing early mobilization, tailored pain management, and close monitoring of metabolic parameters. Despite advancements, knowledge gaps remain, particularly regarding sarcopenic obesity and the long-term impact of preoperative dietary interventions. Future research should focus on refining minimally invasive techniques, integrating personalized medicine, and exploring innovative perioperative protocols to address obesity-related risks effectively. By fostering a multidisciplinary approach, this review underscores the necessity for targeted interventions to enhance outcomes and improve the quality of care for patients with obesity undergoing gastrointestinal cancer surgery.
{"title":"Navigating the weight: The impact of obesity on gastrointestinal cancer surgery and strategies for improved outcomes","authors":"Gerardo Sarno , Claudia Reytor-González , Evelyn Frias-Toral , Martín Campuzano-Donoso , Christos S. Katsanos , Daniel Simancas-Racines","doi":"10.1016/j.semcancer.2025.06.010","DOIUrl":"10.1016/j.semcancer.2025.06.010","url":null,"abstract":"<div><div>Obesity significantly affects gastrointestinal cancer surgery outcomes by creating complex challenges throughout the preoperative, intraoperative, and postoperative stages. This narrative review explores the intricate relationship between obesity and GIC surgery, highlighting the dual burden of obesity as a global public health issue and a determinant of surgical complications. The review aims to analyze physiological and technical hurdles, including limited visibility, prolonged operative times, increased perioperative risks, and adverse recovery outcomes associated with obesity. Evidence emphasizes the critical role of excess visceral fat, systemic inflammation, and insulin resistance in elevating surgical risks. Mitigation strategies involve preoperative nutritional optimization, use of advanced surgical technologies such as robotic-assisted and laparoscopic systems, and individualized postoperative care, encompassing early mobilization, tailored pain management, and close monitoring of metabolic parameters. Despite advancements, knowledge gaps remain, particularly regarding sarcopenic obesity and the long-term impact of preoperative dietary interventions. Future research should focus on refining minimally invasive techniques, integrating personalized medicine, and exploring innovative perioperative protocols to address obesity-related risks effectively. By fostering a multidisciplinary approach, this review underscores the necessity for targeted interventions to enhance outcomes and improve the quality of care for patients with obesity undergoing gastrointestinal cancer surgery.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"114 ","pages":"Pages 138-149"},"PeriodicalIF":12.1,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144519235","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}
Tumor immunotherapy has achieved revolutionary advancements; however, owing to the complex interplay of multiple intrinsic and extrinsic tumor factors, the patient response rate remains suboptimal. Recent research has emphasized the pivotal role of microbiome in tumor progression. Under normal physiological conditions, microbiome enter orally and colonize sites such as the oral and intestinal mucosa, establishing a dynamic microbiome equilibrium that participates in essential physiological processes, including host metabolism and immune regulation. However, in pathological states, including dysbiosis, tumor initiation, or compromised mucosal barrier function, the microbiome can penetrate the mucosal barrier, infiltrate tumor tissues, and engage in intricate direct or indirect interactions with immune cells. These interactions play a pivotal role in reshaping the tumor immune microenvironment and modulating the host's anti-tumor immune response. This review elaborate the regulatory mechanisms involved in direct and indirect interactions between microbiome and immune cells within tumors, and their implications for tumor immunotherapy. We discuss the external factors that impact these interactions and outline the potential use of engineered bacteria in cancer treatment. From the perspective of the interaction network between microbiomes and immune cells, this review elucidates the mechanisms and potential of microbiomes in tumor immunotherapy, offering new insights and potential targets for innovative strategies in tumor prevention and treatment.
{"title":"The microbiome-immune cell interaction network: Advancing tumor immunotherapy","authors":"Wei Liu, Zhou Lan, Zhenzi Lin, Yuyue Zhao, Junxiang Lian, Guangtao Yu","doi":"10.1016/j.semcancer.2025.06.009","DOIUrl":"10.1016/j.semcancer.2025.06.009","url":null,"abstract":"<div><div>Tumor immunotherapy has achieved revolutionary advancements; however, owing to the complex interplay of multiple intrinsic and extrinsic tumor factors, the patient response rate remains suboptimal. Recent research has emphasized the pivotal role of microbiome in tumor progression. Under normal physiological conditions, microbiome enter orally and colonize sites such as the oral and intestinal mucosa, establishing a dynamic microbiome equilibrium that participates in essential physiological processes, including host metabolism and immune regulation. However, in pathological states, including dysbiosis, tumor initiation, or compromised mucosal barrier function, the microbiome can penetrate the mucosal barrier, infiltrate tumor tissues, and engage in intricate direct or indirect interactions with immune cells. These interactions play a pivotal role in reshaping the tumor immune microenvironment and modulating the host's anti-tumor immune response. This review elaborate the regulatory mechanisms involved in direct and indirect interactions between microbiome and immune cells within tumors, and their implications for tumor immunotherapy. We discuss the external factors that impact these interactions and outline the potential use of engineered bacteria in cancer treatment. From the perspective of the interaction network between microbiomes and immune cells, this review elucidates the mechanisms and potential of microbiomes in tumor immunotherapy, offering new insights and potential targets for innovative strategies in tumor prevention and treatment.</div></div>","PeriodicalId":21594,"journal":{"name":"Seminars in cancer biology","volume":"114 ","pages":"Pages 128-137"},"PeriodicalIF":12.1,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144480164","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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