Seminars in oncology最新文献

{"title":"The effects of microbiota-derived short-chain fatty acids on T lymphocytes: From autoimmune diseases to cancer","authors":"Mohamed J. Saadh ,&nbsp;Omer Qutaiba B. Allela ,&nbsp;Suhas Ballal ,&nbsp;Morug Salih Mahdi ,&nbsp;Mamata Chahar ,&nbsp;Rajni Verma ,&nbsp;Rouaida Kadhim A Al-hussein ,&nbsp;Mohaned Adil ,&nbsp;Mahmood Jasem Jawad ,&nbsp;Ali M. Ali Al-Nuaimi","doi":"10.1016/j.seminoncol.2025.152398","DOIUrl":"10.1016/j.seminoncol.2025.152398","url":null,"abstract":"<div><div>Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are the microbial metabolites that have significant functions in host immune modulation, especially T lymphocyte function. Implication by recent evidence indicates SCFAs regulate T-cell growth, differentiation, metabolism, effector function, and apoptosis through histone deacetylase (HDAC) inhibition, G-protein-coupled receptor (GPCR) signaling, and metabolic reprogramming processes. Butyrate, for example, enhances regulatory T cell (Treg) and Interleukin 10 (IL-10)-producing T helper 1 (Th1) cell differentiation as well as context-dependent regulation on T helper 17 (Th17) cell development. SCFAs also impact cytotoxic CD8+ T cells through augmented production of IFN-γ and memory formation, which enhances antiviral and antitumor immunity. SCFAs reprogram T-cell metabolism through enhanced acetyl-CoA, mechanistic target of rapamycin (mTOR) signaling, and fatty acid oxidation (FAO), thus promoting the unique metabolic requirements of effector and memory T-cell subsets. In addition, SCFAs induce apoptosis of activated T cells through the Fas upregulation by inhibiting HDAC1. SCFA dysregulation plays a role in disease and autoimmune disorders like type 1 diabetes and rheumatoid arthritis, whereas therapeutic supplementation reduces inflammation and immune tolerance. SCFAs also amplify the antitumor effect of immune checkpoint inhibitors (eg, anti-programmed cell death protein 1 (anti-PD-1)) in cancer by driving CD8+ T-cell activation, infiltration, and Interferon gamma (IFNγ) production, partially through the transcriptional regulator Inhibitor of DNA binding 2 (ID2). Significantly, tissue- and disease-specific differential expression and functional implication of SCFA receptors (eg, GPR43, GPR41, GPR109A) emphasize the complexity of SCFA-mediated signaling. In conclusion, the current review emphasizes the multifunctional role of microbiota-derived SCFAs in T lymphocyte biology and their therapeutic potential in cancer, infection, and autoimmune diseases.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152398"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MicroRNAs: From bench to bedside applications as breast cancer therapsseutics","authors":"Md Abdus Samad ,&nbsp;Iftikhar Ahmad ,&nbsp;Muhammad Nadeem Asghar ,&nbsp;Mohd Suhail ,&nbsp;Mohd Rehan ,&nbsp;Fahad A. Al-Abbasi ,&nbsp;Khadeejah Alsolami ,&nbsp;Mohd Suhail Akhter ,&nbsp;Ausaf Ahmad ,&nbsp;Shams Tabrez","doi":"10.1016/j.seminoncol.2025.152386","DOIUrl":"10.1016/j.seminoncol.2025.152386","url":null,"abstract":"<div><div>MicroRNAs (miRNAs) or small noncoding RNA molecules, 18–22 nucleotides long, are evolutionarily conserved and may have an impact on the behavior and progression of tumors. Cancer initiation, proliferation, invasion, and metastasis are all related to the specific deregulation of miRNAs. It also affects the genes involved in metabolism, apoptosis, cellular differentiation, and proliferation. Understanding the functional roles of miRNAs could shed light on the intricate molecular mechanism that underlie cancer growth. The purpose of this review is to investigate the presence of tumor-suppressive, oncogenic, and metastatic miRNAs in cancer cells, specifically breast cancer (BC) and how these miRNAs affect the development of BC and its subtypes. In addition, the miRNA-based therapeutic strategies and utilization of different delivery system to enhance the efficacy has also been covered. Based on our article, miRNAs appear to be cutting-edge prognostic, therapeutic, and diagnostic tools for the treatment of BC. However, several barriers, such as, delivery systems, side effects, demographic variabilities, and lengthy clinical studies needs to be optimized before these miRNAs could be routinely used in clinical settings.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152386"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144550081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering autophagy signaling in cancer: A paradigm shift from molecular classifications to clinical innovations.","authors":"Farag M A Altalbawy, Ehab Yassen Theab, Gaurav Sanghvi, R Roopashree, Aditya Kashyap, Hussein Riyadh Abdul Kareem Al-Hetty, S Gayathri, Rajashree Panigrahi, Yasser Fakri Mustafa, Hatif Abdulrazaq Yasin","doi":"10.1016/j.seminoncol.2025.152397","DOIUrl":"10.1016/j.seminoncol.2025.152397","url":null,"abstract":"<p><p>The intracellular breakdown process known as autophagy occurs when cells experience adverse conditions, such as organelle damage, the presence of abnormal proteins, hypoxia stress, low energy levels, or nutritional deprivation. The autophagic process begins by forming autophagosomes, which then merge with lysosomes to recycle degraded materials. Autophagy functions in multiple ways to affect cancer development and treatment outcomes. Tumor cells with low autophagy levels may exhibit anti-tumor effects during cancer initiation because their connection to malignant transformation is possible. The promotion of autophagy appears beneficial for cancer prevention in this context. The survival of cancer cells through increased autophagy enables tumor growth in existing tumors by allowing them to overcome metabolic and treatment-related challenges. Research indicates that blocking autophagy through the use of drugs or genetic methods makes cancer cells more susceptible to chemotherapy, radiation, and targeted therapies, suggesting that inhibiting the autophagic system may be a promising approach to enhance treatment. Excessive autophagy activation could be a therapeutic approach to manage cancer cells that resist cell death. The successful treatment of cancer requires an understanding of autophagy's dual nature. This review examines potential therapeutic strategies for tumors by analyzing autophagy-related signaling pathways and the essential factors that influence cancer development.</p>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"152397"},"PeriodicalIF":6.8,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical efficacy and security analysis of DEB-TACE combined with trans arterial infusion of carrelizumab in the therapy of advanced liver cancer","authors":"Yang Chen,&nbsp;Xinxin Zang,&nbsp;Xiaoxuan Zhang,&nbsp;Songyan Zhang","doi":"10.1016/j.seminoncol.2025.152393","DOIUrl":"10.1016/j.seminoncol.2025.152393","url":null,"abstract":"<div><div>To explore the clinical efficacy and security analysis of DEB-TACE combined with carrelizumab in the therapy of advanced liver cancer. This study was prospectively designed. Using a random number table method, 96 patients with advanced liver cancer hospitalized from August 2022 to August 2023 were divided into the DT group (DEB-TACE treatment, <em>n</em> = 48) and the DT-C group (on the basis of the DT group, receiving carrelizumab infusion via hepatic artery, <em>n</em> = 48). The changes of therapeutic effect, serum tumor markers, T lymphocyte subsets, overall survival (OS) and progression-free survival (PFS) and the adverse effect were observed. The ORR and DCR of the DT-C group were higher than that of the DT group (<em>P</em> &lt; 0.05). After 1 month of treatment, CD3⁺, CD4⁺ and CD4⁺/CD8⁺ were increased and the DT-C group was higher than the DT group (<em>P</em> &lt; 0.001). The CD8+ decreased after 1 month of treatment, and the CD8+ in the DT-C group was significantly lower than that in the DT group (<em>P</em> &lt; 0.001). AFP and PIVKA-II decreased after 1 month of treatment, and the DT-C group was lower than the DT group (<em>P</em> &lt; 0.001). The overall survival (OS) (2-year survival rate 33.33%) and progression-free survival (PFS) (2-year survival rate 18.75%) of the DT-C group were higher than those of the DT group (<em>P</em> &lt; 0.05). There was no difference in the adverse reaction incidence (<em>P</em> &gt; 0.05). DEB-TACE combined with trans arterial infusion of carrelizumab is safe and effective in the treatment of advanced liver cancer. Compared with DEB-TACE alone, this combination therapy results in higher CD3+, CD4+, and CD4+/CD8+ levels, as well as reduced CD8+, AFP, and PIVKA-II levels.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152393"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic reprogramming: The driving force behind cancer drug resistance","authors":"Amr Ali Mohamed Abdelgawwad El-Sehrawy ,&nbsp;Chou-Yi Hsu ,&nbsp;Ali G. Alkhathami ,&nbsp;Muktesh Chandra ,&nbsp;Tina Saeed Basunduwah ,&nbsp;H. Malathi ,&nbsp;Jitendra Narayan Senapati ,&nbsp;Apurav Gautam ,&nbsp;Mundher Kadhem ,&nbsp;Hatif Abdulrazaq Yasin","doi":"10.1016/j.seminoncol.2025.152392","DOIUrl":"10.1016/j.seminoncol.2025.152392","url":null,"abstract":"<div><div>Metabolic reprogramming enables stress adaptation of cancer cells to treatment and is a primary causative force of drug resistance. Dysregulation of glucose, amino acid, and lipid metabolism supplies energy, biosynthetic precursors, and redox balance, promoting survival in the treated tumor. These processes are coordinated by oncogenic signaling, loss of tumor suppressors, and regulatory non-coding RNAs, which promote cancer stemness, immune evasion, and resistance to apoptosis. This review examines the mechanisms by which central metabolic pathways, particularly glycolysis, glutamine metabolism, and fatty acid synthesis, are altered to facilitate drug resistance in various types of cancer. Additionally, we report on novel therapeutic approaches that exploit such metabolic weaknesses to prevent therapy resistance and enhance clinical outcomes. Future directions emphasize the need for advanced metabolic profiling to personalize treatment approaches and the clinical translation of promising preclinical findings to overcome this significant obstacle in cancer therapy.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152392"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144634120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deregulated cell cycle control: The interplay between non-coding RNAs and cyclin-dependent kinases in tumorigenesis","authors":"Chou-Yi Hsu ,&nbsp;Yasir Qasim Almajidi ,&nbsp;Maher abdulrazzaq Al-hakeem ,&nbsp;Mohammad Y. Alshahrani ,&nbsp;Wael Nabil ,&nbsp;Sujayaraj Samuel Jayakumar ,&nbsp;Siya SinglaI ,&nbsp;Zahraa Abbas Al-Khafaji ,&nbsp;Ahmed Remthan Hussein ,&nbsp;Zuhair I. Al-Mashhadani","doi":"10.1016/j.seminoncol.2025.152395","DOIUrl":"10.1016/j.seminoncol.2025.152395","url":null,"abstract":"<div><div>Cyclin-dependent kinases (CDKs) are a group of serine/threonine kinases that are at the center of cell cycle progression. Dysregulated CDK activity, found in a range of human cancers, leads to uncontrolled cell growth and development. Non-coding RNAs (ncRNAs), which include microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are emerging as critical regulators of gene expression and cellular processes, playing an important and often complex role in cancer development and progression. The purpose of this review is to organize knowledge about the interactions of ncRNAs with CDKs, contribution to cancer biology, and to discuss not only the different ways miRNAs target and downregulate CDKs mRNA, leading to inhibition of cell cycle progression and acting as tumor suppressors, but in the case of some miRNAs alter CDK activity as oncogenes by directly upregulating CDK expression or more frequently suppressing the expression of the canonical CDK inhibitors (p21 and p27). Moreover, long non-coding RNAs (lncRNAs) can regulate CDKs through a variety of mechanisms, such as functioning as molecular sponges by absorbing miRNAs that target CDK proteins as miRNA sponges, modulating CDK protein abundance and/or activity indirectly or directly (i.e., the direct interaction with the CDK proteins can potentially invoke an ability to regulate their stability, etc.). Circulating RNAs (circRNAs) also primarily modulate CDK levels and act as inhibitors of the appropriate CDK targeted by a miRNA sponge, potentially through direct interaction with a CDK. Overall, while our understanding of the ncRNA-CDK network is far from complete, the complexities surrounding ncRNA-CDK oncogenic developments and the ability to target these pathways offer significant promise in the harsh realities of cancerogenesis and further therapeutic interventions to fashion more precise cancer therapies that antagonize aberrant cell cycle progression in cancer subtypes.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152395"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application prospects of tumor vaccines for pancreatic cancer: From TAAs to TSAs and combination strategies","authors":"Zerui Lu ,&nbsp;Wenxin Zhu ,&nbsp;Xinjian Liu","doi":"10.1016/j.seminoncol.2025.152399","DOIUrl":"10.1016/j.seminoncol.2025.152399","url":null,"abstract":"<div><div>Pancreatic cancer, a highly aggressive malignancy of the digestive system, exhibits therapeutic resistance due to its immunosuppressive tumor microenvironment (TME) and early metastatic potential. Cancer vaccines targeting tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs) have emerged as promising immunotherapeutic strategies. TAA-based vaccines demonstrate T cell activation and tumor suppression in preclinical models, yet face limitations from antigen heterogeneity and immunosuppressive TME. TSA-directed vaccines, exemplified by personalized mRNA vaccines incorporating whole-exome sequencing-selected neoantigens, achieved long-term recurrence-free survival in 50% of vaccinated patients during phase I/II trials, with phase III data supporting synergistic efficacy when combined with chemotherapy and programmed death receptor 1 (PD-1) inhibitors. KRAS-targeted vaccines address common mutations (e.g., G12D, G12V) to broaden applicability. This review presents an updated summary of current tumor vaccine types, mechanisms, and clinical implications, while analyzing how combination therapies remodel TME infiltration and reverse T cell exhaustion to significantly improve survival outcomes. The discussion also addresses existing challenges and proposes future directions in pancreatic cancer vaccine development.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152399"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144865191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psoas muscle depletion correlates with poor prognosis and compromised immunity in resectable gastric cancer: A multicenter study","authors":"Hao Zhou ,&nbsp;Li Zhong ,&nbsp;Zihan Jin ,&nbsp;Xun Hou ,&nbsp;Haiyun Tang ,&nbsp;Shibin Yang ,&nbsp;Yulong He ,&nbsp;Wu Song ,&nbsp;Changhua Zhang ,&nbsp;Zhewei Wei","doi":"10.1016/j.seminoncol.2025.152400","DOIUrl":"10.1016/j.seminoncol.2025.152400","url":null,"abstract":"<div><div>Sarcopenia, assessed by the psoas muscle index (PMI), is characterized with the loss of skeletal muscle mass and strength, and has gained growing attentions in the field of cancers. However, its role in gastric cancer (GC), especially in patients received gastrectomy, remains underexplored. This multicenter retrospective study examined 439 patients with resectable GC to assess the prognostic significance of sarcopenia, measured by PMI and PMI change rate (PMICR), while also exploring potential links with tumor immunity. Kaplan–Meier analysis revealed that low PMICR was significantly associated with worse survival outcomes in all patient cohorts. Further multivariate Cox analysis identified PMICR (hazard ratio: 2.80, 95% CI: 1.73–4.56), but not baseline PMI—as an independent predictor of overall survival. Immunologically, low PMICR patients exhibited decreased tertiary lymphoid structure density and reduced tumor-infiltrating lymphocytes (CD3+ <em>T</em> cells and CD20+ B cells). The developed nomogram incorporating PMICR showed superior prognostic performance versus TNM stage, with concordance indices of 0.821 (95% CI: 0.789–0.853), 0.800 (95% CI: 0.753–0.847), and 0.816 (95% CI: 0.743–0.889) for training, internal validation, and external validation cohorts, respectively. These results suggested that PMICR, as a measure of sarcopenia, more accurately predicted survival outcomes and might be associated with immune status in resectable GC patients. Moreover, the newly developed nomogram demonstrated high accuracy in predicting prognosis.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152400"},"PeriodicalIF":2.5,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144813888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple myeloma: Insights into underlying mechanisms, advances in diagnostic and therapeutic modalities","authors":"Rohitash Yadav ,&nbsp;Jitendra Kumar Chaudary ,&nbsp;Khushboo Bisht ,&nbsp;Puneet Dhamija ,&nbsp;Pankaj Kumar Chaudhary ,&nbsp;Uttam Kumar Nath ,&nbsp;Neeraj Jain","doi":"10.1016/j.seminoncol.2025.152390","DOIUrl":"10.1016/j.seminoncol.2025.152390","url":null,"abstract":"<div><div>Multiple myeloma (MM) is characterized by malignant proliferation and accumulation of terminally differentiated antibody-producing plasma cells in bone marrow. The underlying genetic causes of MM are highly complex, involving the loss of function in a myriad of crucial genes, especially those involved in DNA replication fidelity and repair. The important genetic events underscoring MM mutagenesis entail large-scale chromosomal aberrations, localized genetic changes, defective DNA repair mechanisms, point mutation, and mutagenic activity of enzymes such as activation-induced deaminase (AID) and apolipoprotein B mRNA editing enzyme, and catalytic polypeptide (APOBEC). Despite considerable improvement in treatment regimen, MM disease remains incurable for majority of patients with very high mortality. Notably, delay in diagnosis of MM could indirectly contribute to the worse clinical outcomes and lower treatment responsiveness through several mechanisms. Primarily, MM diagnosis relies on histopathological changes and molecular profiling of the patient’s sample. In the past decades, new methods of MM diagnosis and therapeutic approaches have been invented. Together, advances in disease understanding, diagnosis, and novel effective therapeutic interventions have substantially helped slow down and/or arresting the disease progression in the large number of patients, thereby increasing overall survival. This review discusses the genetic causes of MM, clinical presentation, advances in diagnosis, and new therapeutic interventions, including combinations of effective agents targeting relapse/refractory MM.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152390"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597079","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the prognostic value and immunotherapeutic strategy of aggrephagy in melanoma: Integrating single-cell sequencing and machine learning","authors":"Zihao Li ,&nbsp;Jiaheng Xie ,&nbsp;Liqun Li ,&nbsp;Yucang He ,&nbsp;Wanying Chen ,&nbsp;Hao Dai ,&nbsp;Songyun Zhao","doi":"10.1016/j.seminoncol.2025.152371","DOIUrl":"10.1016/j.seminoncol.2025.152371","url":null,"abstract":"<div><div>This study aimed to investigate the role of aggrephagy in cutaneous melanoma (CM) and explore its potential as a biomarker for prognosis and therapeutic targeting. We utilized single-cell sequencing technology and machine learning algorithms to analyze melanoma transcriptome data from the TCGA database and validated our findings using 3 independent datasets from the GEO database. By employing enrichment scoring in single-cell sequencing, we identified characteristic expression patterns of different cell types involved in aggrephagy and constructed an aggrephagy-related signature (ARS). We further evaluated the association of ARS with clinical features, immune cell infiltration, tumor mutational load (TMB), and immune checkpoint gene expression. Additionally, we conducted in vivo experiments by knocking down TPX2, the most critical oncogene in ARS, using shRNA and assessed its effects on tumor proliferation and T-cell growth via subcutaneous tumor formation assays and flow cytometry in mice. The ARS demonstrated robust prognostic predictive power across multiple datasets, with higher ARS scores associated with poorer overall survival (OS) and lower levels of immune cell infiltration. Patients with low ARS scores were more likely to benefit from immune checkpoint inhibitor therapies, while those with high scores exhibited increased sensitivity to 2 common chemotherapeutic agents. Compared to published melanoma prognostic models, our ARS showed higher accuracy and stability. The construction of an ARS-related nomogram further facilitated more accurate clinical decision-making. In vivo experiments confirmed that TPX2 knockdown inhibited tumor proliferation and enhanced T-cell growth, highlighting its critical role in CM progression. Our study highlights the complex functions of the aggrephagy-related signature in cutaneous melanoma, underscoring its potential as a therapeutic target and a valuable tool for prognostic assessment.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 5","pages":"Article 152371"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144670408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}