Raf-1 Kinase Inhibitor Protein (RKIP) is a well-known metastasis suppressor that regulates key oncogenic signaling pathways. Emerging evidence also points to a dual role for RKIP as an immunomodulatory molecule, influencing the tumor immune microenvironment, a complex niche that promotes immune evasion and overall tumor progression. This review explores RKIP's impact on immune surveillance via its interactions with signaling pathways and cellular components of the tumor microenvironment, as well as its role in recruiting and polarizing immune cells with different dynamics in reshaping an immunocompetent milieu. We further discuss how RKIP downregulation promotes immune evasion, alters cytokine profiles, and reduces effector immune cell infiltration. Current studies suggest that RKIP supports type I interferon signaling and antigen presentation, while its loss contributes to an immunosuppressive, pro-metastatic environment. Therefore, by regulating the expression of RKIP in the pathways that control TME architecture, the TME can be reprogramed towards an immunoprotected milieu. Altogether, this review underscores RKIP's role in tumor immunity, offering new perspectives for therapeutic strategies aimed at overcoming cancer immune evasion and improving immunotherapy efficacy.
{"title":"RKIP and tumor immune evasion: Remodeling the immunosuppressive tumor microenvironment","authors":"Evagelia Skouradaki , Giasemi C. Eptaminitaki , Evagelia Kirio , Apostolos Zaravinos , Nikolas Dovrolis , Stavroula Baritaki","doi":"10.1016/j.bbcan.2025.189481","DOIUrl":"10.1016/j.bbcan.2025.189481","url":null,"abstract":"<div><div>Raf-1 Kinase Inhibitor Protein (RKIP) is a well-known metastasis suppressor that regulates key oncogenic signaling pathways. Emerging evidence also points to a dual role for RKIP as an immunomodulatory molecule, influencing the tumor immune microenvironment, a complex niche that promotes immune evasion and overall tumor progression. This review explores RKIP's impact on immune surveillance via its interactions with signaling pathways and cellular components of the tumor microenvironment, as well as its role in recruiting and polarizing immune cells with different dynamics in reshaping an immunocompetent milieu. We further discuss how RKIP downregulation promotes immune evasion, alters cytokine profiles, and reduces effector immune cell infiltration. Current studies suggest that RKIP supports type I interferon signaling and antigen presentation, while its loss contributes to an immunosuppressive, pro-metastatic environment. Therefore, by regulating the expression of RKIP in the pathways that control TME architecture, the TME can be reprogramed towards an immunoprotected milieu. Altogether, this review underscores RKIP's role in tumor immunity, offering new perspectives for therapeutic strategies aimed at overcoming cancer immune evasion and improving immunotherapy efficacy.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189481"},"PeriodicalIF":9.7,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145350384","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 : 2025-10-17DOI: 10.1016/j.bbcan.2025.189479
José R. Almeida , Edgar.A. Pinos-Tamayo , Bruno Mendes , Alberto A. Robles-Loaiza , Rony Abdi Syahputra , Ana Gabriela Silva Oliveira , Rosy Iara Maciel de A. Ribeiro
Cancer treatment has come a long way, but not all cancers can be completely cured. The current therapeutic landscape has significantly reduced mortality rates; however, it remains associated with side effects, limited accessibility, financial burden, drug shortages, and emotional as well as mental health consequences for patients. Hence, despite significant advances, the development of novel therapies remains a focal point of research. In this review, we explore the current state of snake venom-inspired peptides as templates for the design of much-needed innovative anticancer agents. Initially, we examine conventional cancer treatments, their main challenges, and the niche filled by newly approved peptide-based therapies. Then, we present a high-level overview of the potential of snake venoms as broad-spectrum libraries of bioactive components and discuss a roadmap for mining these rich and complex mixtures to pioneer the next generation of cancer drugs, leading to the emergence of “oncovenomics”. Harnessing the potential of modern in silico approaches, we delve into the structure, biochemical parameters, and bioactivity of venom-inspired peptides. Our research identified more than 30 snake venom-derived peptides with micromolar lytic action against different cancer cells, including solid and liquid tumours. Transitioning from in vitro monolayer analyses to clinical settings remains an unfulfilled goal, with the majority of studies failing to progress to more advanced stages, including the preclinical phase involving in vivo experiments. Here, we also describe how artificial intelligence, and the integration of other cutting-edge technologies can provide an expandable framework for translating the high in vitro potential of venom-derived peptides into clinically useful therapies. Lastly, we examined the translational challenges and the strategies proposed to overcome them. In summary, snake venom-derived peptides are attractive scaffolds for drug discovery programs, demonstrating historical benefits. However, overcoming the existing barriers in their development requires further multidisciplinary efforts. On the horizon, advances in high-throughput research tools and peptide engineering strategies offer opportunities for introducing next-generation venom peptide-based therapeutics to address cancer in clinical practice.
{"title":"Snake venom-derived peptides as anticancer candidates: Pioneering next-generation therapies","authors":"José R. Almeida , Edgar.A. Pinos-Tamayo , Bruno Mendes , Alberto A. Robles-Loaiza , Rony Abdi Syahputra , Ana Gabriela Silva Oliveira , Rosy Iara Maciel de A. Ribeiro","doi":"10.1016/j.bbcan.2025.189479","DOIUrl":"10.1016/j.bbcan.2025.189479","url":null,"abstract":"<div><div>Cancer treatment has come a long way, but not all cancers can be completely cured. The current therapeutic landscape has significantly reduced mortality rates; however, it remains associated with side effects, limited accessibility, financial burden, drug shortages, and emotional as well as mental health consequences for patients. Hence, despite significant advances, the development of novel therapies remains a focal point of research. In this review, we explore the current state of snake venom-inspired peptides as templates for the design of much-needed innovative anticancer agents. Initially, we examine conventional cancer treatments, their main challenges, and the niche filled by newly approved peptide-based therapies. Then, we present a high-level overview of the potential of snake venoms as broad-spectrum libraries of bioactive components and discuss a roadmap for mining these rich and complex mixtures to pioneer the next generation of cancer drugs, leading to the emergence of “oncovenomics”. Harnessing the potential of modern <em>in silico</em> approaches, we delve into the structure, biochemical parameters, and bioactivity of venom-inspired peptides. Our research identified more than 30 snake venom-derived peptides with micromolar lytic action against different cancer cells, including solid and liquid tumours. Transitioning from <em>in vitro</em> monolayer analyses to clinical settings remains an unfulfilled goal, with the majority of studies failing to progress to more advanced stages, including the preclinical phase involving <em>in vivo</em> experiments. Here, we also describe how artificial intelligence, and the integration of other cutting-edge technologies can provide an expandable framework for translating the high <em>in vitro</em> potential of venom-derived peptides into clinically useful therapies. Lastly, we examined the translational challenges and the strategies proposed to overcome them. In summary, snake venom-derived peptides are attractive scaffolds for drug discovery programs, demonstrating historical benefits. However, overcoming the existing barriers in their development requires further multidisciplinary efforts. On the horizon, advances in high-throughput research tools and peptide engineering strategies offer opportunities for introducing next-generation venom peptide-based therapeutics to address cancer in clinical practice.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189479"},"PeriodicalIF":9.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145331115","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 : 2025-10-15DOI: 10.1016/j.bbcan.2025.189477
Jiahao Xu , Yujie Jin , Shiqiang Liu , Lizhuo Wang , Jialin Gao
Tumor progression is closely related to the complex interactive regulation between autophagy and apoptosis signaling pathways, particularly the molecular mechanisms mediated by lysosomal membrane proteins (LMPs), and their dynamic regulatory processes have become an important direction of current research. However, there is a lack of in-depth and systematic reviews on this topic. This review focuses on the multi-dimensional mechanisms by which LMPs mediate the regulation of the autophagy–apoptosis crosstalk via key molecules like Beclin1, Autophagy-related (ATG), Caspase, PARP, and Bax/Bcl-2 in tumor progression. In addition, it highlights their roles in signaling pathways, drug-mediated cell cycle and combination therapy mechanisms, autophagic and apoptotic crosstalk underlying synergistic and antagonistic effects, and other key biological processes. Overall, as the core hub of the autophagy–apoptosis crosstalk network, the multifactorial synergistic effect mediated by LMPs is crucial in tumor progression. In-depth analysis of this mechanism not only elucidates the molecular pathological basis of tumorigenesis but also provides a theoretical basis for the development of novel anti-tumor intervention strategies targeting LMPs.
{"title":"Dissecting the dual roles of lysosomal membrane proteins: Mediators of autophagy–apoptosis crosstalk in tumor progression","authors":"Jiahao Xu , Yujie Jin , Shiqiang Liu , Lizhuo Wang , Jialin Gao","doi":"10.1016/j.bbcan.2025.189477","DOIUrl":"10.1016/j.bbcan.2025.189477","url":null,"abstract":"<div><div>Tumor progression is closely related to the complex interactive regulation between autophagy and apoptosis signaling pathways, particularly the molecular mechanisms mediated by lysosomal membrane proteins (LMPs), and their dynamic regulatory processes have become an important direction of current research. However, there is a lack of in-depth and systematic reviews on this topic. This review focuses on the multi-dimensional mechanisms by which LMPs mediate the regulation of the autophagy–apoptosis crosstalk <em>via</em> key molecules like Beclin1, Autophagy-related (ATG), Caspase, PARP, and Bax/Bcl-2 in tumor progression. In addition, it highlights their roles in signaling pathways, drug-mediated cell cycle and combination therapy mechanisms, autophagic and apoptotic crosstalk underlying synergistic and antagonistic effects, and other key biological processes. Overall, as the core hub of the autophagy–apoptosis crosstalk network, the multifactorial synergistic effect mediated by LMPs is crucial in tumor progression. In-depth analysis of this mechanism not only elucidates the molecular pathological basis of tumorigenesis but also provides a theoretical basis for the development of novel anti-tumor intervention strategies targeting LMPs.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189477"},"PeriodicalIF":9.7,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145314116","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 : 2025-10-14DOI: 10.1016/j.bbcan.2025.189475
Małgorzata Figiel , Katarzyna Pustelny , Marta Dziedzicka-Wasylewska , Rendy Hosea , Vivi Kasim , Andrzej Górecki
The transcription factors Yin Yang 1 and Yin Yang 2 are key regulators of gene expression and play complex roles in cancer development. Although closely related in sequence and structure, YY1 and YY2 differ in their degree of intrinsic disorder, interaction profiles, and regulatory potential. Both proteins are subject to cancer-associated alterations, including changes in expression levels and somatic mutations, many of which correlate with clinical outcomes.
This review synthesizes a comparative analysis of YY1 and YY2, with a focus on their disordered regions, interaction networks, and promoter targeting mechanisms. YY1 exhibits a higher degree of intrinsic disorder and a greater number of predicted Molecular Recognition Features (MoRFs), enabling a broader and more competitive range of interactions. YY2, in contrast, is more structurally ordered and engages a more limited set of partners. While both proteins recognize specific and highly similar DNA motifs, their binding is relatively weak, and functional specificity is conferred primarily through distinct protein–protein interactions and regulatory complex assembly.
We integrate these findings within the framework of Brodsky's model of promoter recognition, which emphasizes the role of dynamic, cooperative interactions in guiding transcription factor specificity. By mapping cancer-associated mutations and post-translational modifications onto functional regions, we highlight how such alterations may disrupt interaction networks and promoter selection. Finally, we explore the therapeutic potential of selectively targeting YY1/YY2 interactions, despite the challenges posed by their intrinsically disordered domains.
{"title":"Unstructured but critical: The role of YY1 and YY2 disorder in promoter recognition networks, transcriptional control, and oncogenesis","authors":"Małgorzata Figiel , Katarzyna Pustelny , Marta Dziedzicka-Wasylewska , Rendy Hosea , Vivi Kasim , Andrzej Górecki","doi":"10.1016/j.bbcan.2025.189475","DOIUrl":"10.1016/j.bbcan.2025.189475","url":null,"abstract":"<div><div>The transcription factors Yin Yang 1 and Yin Yang 2 are key regulators of gene expression and play complex roles in cancer development. Although closely related in sequence and structure, YY1 and YY2 differ in their degree of intrinsic disorder, interaction profiles, and regulatory potential. Both proteins are subject to cancer-associated alterations, including changes in expression levels and somatic mutations, many of which correlate with clinical outcomes.</div><div>This review synthesizes a comparative analysis of YY1 and YY2, with a focus on their disordered regions, interaction networks, and promoter targeting mechanisms. YY1 exhibits a higher degree of intrinsic disorder and a greater number of predicted Molecular Recognition Features (MoRFs), enabling a broader and more competitive range of interactions. YY2, in contrast, is more structurally ordered and engages a more limited set of partners. While both proteins recognize specific and highly similar DNA motifs, their binding is relatively weak, and functional specificity is conferred primarily through distinct protein–protein interactions and regulatory complex assembly.</div><div>We integrate these findings within the framework of Brodsky's model of promoter recognition, which emphasizes the role of dynamic, cooperative interactions in guiding transcription factor specificity. By mapping cancer-associated mutations and post-translational modifications onto functional regions, we highlight how such alterations may disrupt interaction networks and promoter selection. Finally, we explore the therapeutic potential of selectively targeting YY1/YY2 interactions, despite the challenges posed by their intrinsically disordered domains.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189475"},"PeriodicalIF":9.7,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310171","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 : 2025-10-14DOI: 10.1016/j.bbcan.2025.189478
Yafei Li , Lingao Zhu , Lu Liu, Bo Li
Macrophages play a dual role of promoting or inhibiting in inflammation and tumor progression, highly dependent on the dynamic changes of M1/M2 polarization. In inflammation, M1/M2 polarization balance determines the outbreak of inflammation or tissue repair. In the tumor microenvironment, M1 tumor-associated macrophages (TAMs) exert both anti-tumor and pro-tumor effects, while M2 TAMs promote tumor progression. PKM2 regulates the M1/M2 polarization and cytokine secretion of macrophages through the pyruvate kinase activity of tetramers as well as the protein kinase activity and transcriptional co-activator function of dimers. This review summarizes the role and molecular mechanism of macrophage PKM2 in inflammation and tumor progression, highlighting its potential as a therapeutic target in inflammatory diseases and cancers. Macrophage PKM2 plays a promoting role in inflammation and tumor progression due to its dual regulatory characteristics of metabolism and immunity. It can not only meet the energy demands of macrophages through glycolytic metabolism, but also affect the immune response through enzyme activity-dependent and non-dependent mechanisms. The non-enzyme activity-dependent mechanism by which PKM2 regulates immune responses serves as a bridge connecting cellular metabolism and immune responses. The unresolved issues include the functional heterogeneity of macrophage PKM2 across different macrophage subtypes, its specific roles in lipid and amino acid metabolism, its contribution to tumor microenvironmental metabolic reprogramming, and PKM2-mediated interactions of macrophages with other cells.
{"title":"Role of macrophage PKM2 in inflammation and tumor progression and its targeted therapy","authors":"Yafei Li , Lingao Zhu , Lu Liu, Bo Li","doi":"10.1016/j.bbcan.2025.189478","DOIUrl":"10.1016/j.bbcan.2025.189478","url":null,"abstract":"<div><div>Macrophages play a dual role of promoting or inhibiting in inflammation and tumor progression, highly dependent on the dynamic changes of M1/M2 polarization. In inflammation, M1/M2 polarization balance determines the outbreak of inflammation or tissue repair. In the tumor microenvironment, M1 tumor-associated macrophages (TAMs) exert both anti-tumor and pro-tumor effects, while M2 TAMs promote tumor progression. PKM2 regulates the M1/M2 polarization and cytokine secretion of macrophages through the pyruvate kinase activity of tetramers as well as the protein kinase activity and transcriptional co-activator function of dimers. This review summarizes the role and molecular mechanism of macrophage PKM2 in inflammation and tumor progression, highlighting its potential as a therapeutic target in inflammatory diseases and cancers. Macrophage PKM2 plays a promoting role in inflammation and tumor progression due to its dual regulatory characteristics of metabolism and immunity. It can not only meet the energy demands of macrophages through glycolytic metabolism, but also affect the immune response through enzyme activity-dependent and non-dependent mechanisms. The non-enzyme activity-dependent mechanism by which PKM2 regulates immune responses serves as a bridge connecting cellular metabolism and immune responses. The unresolved issues include the functional heterogeneity of macrophage PKM2 across different macrophage subtypes, its specific roles in lipid and amino acid metabolism, its contribution to tumor microenvironmental metabolic reprogramming, and PKM2-mediated interactions of macrophages with other cells.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189478"},"PeriodicalIF":9.7,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145310194","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 : 2025-10-10DOI: 10.1016/j.bbcan.2025.189474
Nasot Rashed , Wenbin Liu , Xiangjian Luo
Fatty acid oxidation (FAO), or β-oxidation, is a catabolic process that breaks down fatty acids into acetyl-CoA. FAO plays a pivotal role in the metabolic reprogramming of cancer cells and the tumor microenvironment (TME), serving as a crucial energy source that sustains cellular functions under conditions of nutrient deprivation and metabolic stress. This process significantly influences cancer cell survival, proliferation, metastasis, and therapeutic resistance. In this review, we discuss the biological functions of FAO in cancer cells, immune cells, and stromal cells, with a particular focus on its regulatory role in tumor progression and therapy resistance. Furthermore, we explore FAO inhibitors and emerging therapeutic strategies targeting FAO as a potential approach to disrupting tumor metabolism and enhancing cancer treatment efficacy.
{"title":"The role of fatty acid oxidation in the tumor microenvironment: Implications for cancer progression and therapeutic strategies","authors":"Nasot Rashed , Wenbin Liu , Xiangjian Luo","doi":"10.1016/j.bbcan.2025.189474","DOIUrl":"10.1016/j.bbcan.2025.189474","url":null,"abstract":"<div><div>Fatty acid oxidation (FAO), or <em>β</em>-oxidation, is a catabolic process that breaks down fatty acids into acetyl-CoA. FAO plays a pivotal role in the metabolic reprogramming of cancer cells and the tumor microenvironment (TME), serving as a crucial energy source that sustains cellular functions under conditions of nutrient deprivation and metabolic stress. This process significantly influences cancer cell survival, proliferation, metastasis, and therapeutic resistance. In this review, we discuss the biological functions of FAO in cancer cells, immune cells, and stromal cells, with a particular focus on its regulatory role in tumor progression and therapy resistance. Furthermore, we explore FAO inhibitors and emerging therapeutic strategies targeting FAO as a potential approach to disrupting tumor metabolism and enhancing cancer treatment efficacy.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189474"},"PeriodicalIF":9.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276897","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 : 2025-10-10DOI: 10.1016/j.bbcan.2025.189472
Tianguang Cheng , Min Pan , Yi Qiao , Jing Tu
Mitochondrial DNA (mtDNA) is crucial for cellular metabolism, oxidative stress responses, and genomic stability, with mutations linked to cancer progression and therapeutic resistance. Mitochondrial heteroplasmy, the coexistence of wild-type and mutant mtDNA within a cell or across populations, plays a key role in mitochondrial dysfunction, tumor heterogeneity, and disease pathogenesis. Advances in single-cell technologies like quantitative PCR (qPCR), digital droplet PCR (ddPCR), next-generation sequencing (NGS), and long-read sequencing (TGS) have enabled precise mapping of heteroplasmic variants, providing insights into their role in cancer. This review evaluates current detection methods, discussing their strengths, limitations, and relevance to cancer research. We also explore the biological implications of heteroplasmy in cellular dynamics, nuclear mitochondrial DNA segments (NUMTs), and cancer pathogenesis, highlighting emerging technologies and future directions for studying mtDNA mutations at single-cell resolution in cancer. Ultimately, this review provides a critical synthesis of how single-cell mtDNA heteroplasmy analysis is reshaping our understanding of tumorigenesis and identifies key methodological and challenges that must be addressed to realize its full potential in precision oncology.
{"title":"Detection methods for mitochondrial DNA heteroplasmy and their potential single-cell applications in cancer","authors":"Tianguang Cheng , Min Pan , Yi Qiao , Jing Tu","doi":"10.1016/j.bbcan.2025.189472","DOIUrl":"10.1016/j.bbcan.2025.189472","url":null,"abstract":"<div><div>Mitochondrial DNA (mtDNA) is crucial for cellular metabolism, oxidative stress responses, and genomic stability, with mutations linked to cancer progression and therapeutic resistance. Mitochondrial heteroplasmy, the coexistence of wild-type and mutant mtDNA within a cell or across populations, plays a key role in mitochondrial dysfunction, tumor heterogeneity, and disease pathogenesis. Advances in single-cell technologies like quantitative PCR (qPCR), digital droplet PCR (ddPCR), next-generation sequencing (NGS), and long-read sequencing (TGS) have enabled precise mapping of heteroplasmic variants, providing insights into their role in cancer. This review evaluates current detection methods, discussing their strengths, limitations, and relevance to cancer research. We also explore the biological implications of heteroplasmy in cellular dynamics, nuclear mitochondrial DNA segments (NUMTs), and cancer pathogenesis, highlighting emerging technologies and future directions for studying mtDNA mutations at single-cell resolution in cancer. Ultimately, this review provides a critical synthesis of how single-cell mtDNA heteroplasmy analysis is reshaping our understanding of tumorigenesis and identifies key methodological and challenges that must be addressed to realize its full potential in precision oncology.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189472"},"PeriodicalIF":9.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145282154","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}
Mitochondria in natural killer (NK) cells orchestrate a dynamic interplay between energy production and immune regulation, placing them at the forefront of oncogenesis and tumor microenvironment (TME) infiltration. This review unravels the intricate disruptions in mitochondrial dynamics—fission, fusion, and biogenesis—that hypoxia imposes within the TME, culminating in impaired NK cell functionality. Hypoxia-driven mitochondrial fragmentation, mediated by HIF-1α and mTOR-Drp1 signaling, cripples NK cell cytotoxicity, proliferation, and maturation, while elevated ROS levels and metabolic reprogramming bolster tumor immune evasion. The metabolic landscape of the TME adds another layer of complexity, with amino acid depletion significantly hindering NK cell performance. Arginine and leucine deficiencies suppress proliferation and mTOR activation, whereas disrupted glutamine metabolism impairs cMyc-driven metabolic adaptation. Additionally, immunosuppressive catabolites like nitric oxide and L-kynurenine exacerbate NK cell dysfunction by curbing cytokine production and receptor expression. Targeting these metabolic vulnerabilities offers a promising strategy; specifically, interventions aimed at amino acid pathways could simultaneously restrict nutrient availability within the tumor microenvironment and preserve NK cell functionalities. Emerging strategies spotlight the potential of NK cells to induce autophagic death in hypoxic cancer cells, a mechanism that could restore their cytotoxic potential. Furthermore, immune checkpoint pathways, such as PD-1 and CTLA-4, amplify mitochondrial dysfunction, underscoring their therapeutic significance. By addressing hypoxia, metabolic dysregulation, and mitochondrial reprogramming, this review illuminates actionable strategies to reinvigorate NK cell-mediated antitumor responses and pave the way for transformative cancer therapies.
{"title":"Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression","authors":"Sayak Ghosh , Rittick Dutta , Devyani Goswami , Debapriya Ghatak , Rudranil De","doi":"10.1016/j.bbcan.2025.189471","DOIUrl":"10.1016/j.bbcan.2025.189471","url":null,"abstract":"<div><div>Mitochondria in natural killer (NK) cells orchestrate a dynamic interplay between energy production and immune regulation, placing them at the forefront of oncogenesis and tumor microenvironment (TME) infiltration. This review unravels the intricate disruptions in mitochondrial dynamics—fission, fusion, and biogenesis—that hypoxia imposes within the TME, culminating in impaired NK cell functionality. Hypoxia-driven mitochondrial fragmentation, mediated by HIF-1α and mTOR-Drp1 signaling, cripples NK cell cytotoxicity, proliferation, and maturation, while elevated ROS levels and metabolic reprogramming bolster tumor immune evasion. The metabolic landscape of the TME adds another layer of complexity, with amino acid depletion significantly hindering NK cell performance. Arginine and leucine deficiencies suppress proliferation and mTOR activation, whereas disrupted glutamine metabolism impairs cMyc-driven metabolic adaptation. Additionally, immunosuppressive catabolites like nitric oxide and L-kynurenine exacerbate NK cell dysfunction by curbing cytokine production and receptor expression. Targeting these metabolic vulnerabilities offers a promising strategy; specifically, interventions aimed at amino acid pathways could simultaneously restrict nutrient availability within the tumor microenvironment and preserve NK cell functionalities. Emerging strategies spotlight the potential of NK cells to induce autophagic death in hypoxic cancer cells, a mechanism that could restore their cytotoxic potential. Furthermore, immune checkpoint pathways, such as PD-1 and CTLA-4, amplify mitochondrial dysfunction, underscoring their therapeutic significance. By addressing hypoxia, metabolic dysregulation, and mitochondrial reprogramming, this review illuminates actionable strategies to reinvigorate NK cell-mediated antitumor responses and pave the way for transformative cancer therapies.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189471"},"PeriodicalIF":9.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276830","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 : 2025-10-10DOI: 10.1016/j.bbcan.2025.189473
Xinran Liu , Qiujin Ma , Zhao Jia , Churong Zou , Kun Huang
Interferon-stimulated gene product 15 (ISG15) is a ubiquitin-like protein. It functions as a conjugated form by covalently modifying target proteins (ISGylation), or in a free form, both are involved in a broad variety of cellular processes. Increasing studies report the critical and complex roles of ISG15 in cancer progression and development. Herein, based on its conjugated or free form, we summarize ISG15-related oncogenic characteristics, such as cancer stemness, invasion and metastasis, anti-apoptosis and cancer drug resistance, and review ISG15-regulated oncogenic pathways, highlighting the molecular regulations of ISG15 in different cancers. This review aims to provide new insights into how ISG15 affects tumor pathogenesis, and propose potential cancer interventions targeting ISG15.
{"title":"The multifaceted roles of ISG15 in cancer: Conjugated and free forms","authors":"Xinran Liu , Qiujin Ma , Zhao Jia , Churong Zou , Kun Huang","doi":"10.1016/j.bbcan.2025.189473","DOIUrl":"10.1016/j.bbcan.2025.189473","url":null,"abstract":"<div><div>Interferon-stimulated gene product 15 (ISG15) is a ubiquitin-like protein. It functions as a conjugated form by covalently modifying target proteins (ISGylation), or in a free form, both are involved in a broad variety of cellular processes. Increasing studies report the critical and complex roles of ISG15 in cancer progression and development. Herein, based on its conjugated or free form, we summarize ISG15-related oncogenic characteristics, such as cancer stemness, invasion and metastasis, anti-apoptosis and cancer drug resistance, and review ISG15-regulated oncogenic pathways, highlighting the molecular regulations of ISG15 in different cancers. This review aims to provide new insights into how ISG15 affects tumor pathogenesis, and propose potential cancer interventions targeting ISG15.</div></div>","PeriodicalId":8782,"journal":{"name":"Biochimica et biophysica acta. Reviews on cancer","volume":"1880 6","pages":"Article 189473"},"PeriodicalIF":9.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276851","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 : 2025-10-09DOI: 10.1016/j.bbcan.2025.189470
Lei Yang , Ying Gan , Yu Fan , Qian Zhang
Zinc finger proteins (ZNFs), among the most expansive families of transcription factors in eukaryotes, are distinguished by their distinctive zinc-coordinated motifs, which facilitate intricate interactions with DNA, RNA, and other proteins. These multifaceted interactions are central to their roles in regulating gene expression and modulating key signaling pathways, thus governing a spectrum of cellular processes such as differentiation, proliferation, and apoptosis. Recent studies have elucidated the crucial involvement of ZNFs in the pathogenesis of urological malignancies, including kidney, bladder, and prostate cancers. The inherent complexity and heterogeneity of these cancers necessitate an in-depth exploration of the molecular mechanisms underpinning tumor progression, with ZNFs emerging as central regulators in both oncogenic and tumor-suppressive capacities. This review provides a comprehensive examination of the diverse roles of ZNFs in urological cancers, highlighting their mechanistic actions, interactions with pivotal signaling networks, and contributions to the tumorigenic landscape. Furthermore, it delves into the translational potential of ZNFs, contemplating their utility as diagnostic biomarkers, prognostic tools, and promising therapeutic targets in clinical oncology.
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