Seminars in oncology最新文献

{"title":"Recent updates on novel heterocyclic scaffolds of anticancer potential as emerging tubulin inhibitors","authors":"Sahil Kumar ,&nbsp;Urvashi Gupta ,&nbsp;Rajesh Kumar Singh","doi":"10.1016/j.seminoncol.2025.152374","DOIUrl":"10.1016/j.seminoncol.2025.152374","url":null,"abstract":"<div><div>Cancer remains a leading cause of mortality worldwide, accounting for approximately one in six deaths. Among the most prevalent cancer types are prostate, lung, colon, and rectal cancers. Despite significant investments in research, the therapeutic success of modern cancer treatments remains limited compared to other life-threatening diseases. In the pursuit of novel anticancer strategies, microtubules—dynamic cytoskeletal structures essential for cellular processes such as mitosis, intracellular transport, and signaling—have emerged as attractive drug targets. This review provides a comprehensive overview of recent advancements in the design and synthesis of novel heterocyclic scaffolds as tubulin inhibitors, emphasizing their potential as anticancer agents. Heterocyclic compounds exhibit unique therapeutic properties that disrupt microtubule dynamics, inducing cell cycle arrest and apoptosis in rapidly proliferating cancer cells. The article systematically classifies and critically evaluates diverse heterocyclic scaffolds, including both natural products and synthetic derivatives, with a focus on their interactions with the microtubule cytoskeleton at a molecular level. By consolidating current insights into these emerging scaffolds, this review serves as a valuable resource for the development of next-generation anticancer therapeutics targeting tubulin.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152374"},"PeriodicalIF":3.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144472025","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":"Breast cancer exosomes: Managing macrophage polarization and immune regulation in the tumor microenvironment","authors":"Suleiman Ibrahim Mohammad ,&nbsp;Ehab Yassen Theab ,&nbsp;Asokan Vasudevan ,&nbsp;Ashok Kumar Bishoyi ,&nbsp;Suhas Ballal ,&nbsp;Hussein Riyadh Abdul Kareem Al-Hetty ,&nbsp;Aman Shankhyan ,&nbsp;Anupria A ,&nbsp;Rajashree Panigrahi ,&nbsp;Hatif Abdulrazaq Yasin","doi":"10.1016/j.seminoncol.2025.152365","DOIUrl":"10.1016/j.seminoncol.2025.152365","url":null,"abstract":"<div><div>Exosomes are sub-150 nm extracellular vesicles mediating intercellular messaging in breast cancer's complex tumor microenvironment (TME). Produced by both tumor cells and their stroma components, these vesicles excrete various biomolecules, such as microRNAs (miRNAs), proteins, lipids, and even DNA fragments, enabling a functional exchange of information among cells. In breast cancer, different studies indicate a significant role of exosome-mediated signaling in modulating the phenotype of tumor-associated macrophages (TAMs), mainly polarizing them toward an M2-like phenotype, further supporting the potentiality for tumor-promoting functions. This review will detail the diverse roles of breast cancer-derived exosomes and macrophage polarization and elaborate on their recognized pathways by which these vesicles casually alter the macrophage phenotype. In our discussion, we take a broad detour to deeply examine the unique molecular accessories delivered by breast cancer exosomes. In particular, we discuss the miRNAs suppressed by M1-associated gene expression and those endowing M2-related pathways with abilities, and we cover the proteins that activate pathways like the STAT3 and NF-κB pathways in macrophages. This review will also address the relevance of mechanistic issues to clinical manifestation in exosome-mediated macrophage polarization in breast cancer. Finally, targeting exosome-mediated macrophage polarization as a promising strategy to enhance antitumor immunity in conjunction with improving breast cancer outcomes is deliberated.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152365"},"PeriodicalIF":3.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144322977","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":"Unlocking the therapeutic potential of polyphenols: Promising advances and future directions in pancreatic cancer treatment","authors":"Mohd Suhail ,&nbsp;Shams Tabrez ,&nbsp;Mohammad Tarique ,&nbsp;Naoshad Muhammad ,&nbsp;Mohd Rehan ,&nbsp;Torki A. Zughaibi ,&nbsp;Mohammad Hassan Alhashmi","doi":"10.1016/j.seminoncol.2025.152353","DOIUrl":"10.1016/j.seminoncol.2025.152353","url":null,"abstract":"<div><div>Pancreatic cancer is one of the most lethal malignancies of the digestive tract, with a poor prognosis and a 5-year survival rate of less than 10%. The highly aggressive nature of pancreatic cancer results in a mortality rate of approximately 50% within the 6-month period of diagnosis. The absence of disease-specific symptoms significantly impedes early detection and timely intervention, contributing to its high mortality rate. Current treatment options such as radiotherapy, chemotherapy, and surgery are often inadequate for complete disease eradication and are associated with severe side effects that compromise patients' overall health. As a result, there is an urgent need for novel therapeutic strategies to address the rapidly increasing incidence of pancreatic cancer while ensuring safer, cost and more effective treatment alternatives. Plant-derived polyphenols have emerged as promising candidates due to their potent anticancer properties and minimal side effects compared to conventional therapies. In this review, we explore the biological significance and anticancer mechanisms of key polyphenols, including quercetin, resveratrol, apigenin, luteolin, EGCG, and curcumin, with a particular focus on their role in combating pancreatic cancer. Additionally, we provide a comprehensive summary of various pancreatic cancer studies, including ongoing clinical trials from the past decade.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152353"},"PeriodicalIF":3.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144313674","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":"Exosomal circular RNAs as drivers of temozolomide resistance in glioblastoma: Mechanisms and implications","authors":"Ehab Yassen Theab ,&nbsp;Ali G. Alkhathami ,&nbsp;Inas Ridha Ali ,&nbsp;Hussein Riyadh Abdul Kareem Al-Hetty ,&nbsp;Suhas Ballal ,&nbsp;Rishiv Kalia ,&nbsp;Sami G. Almalki ,&nbsp;Renu Arya ,&nbsp;Deepak Nathiya","doi":"10.1016/j.seminoncol.2025.152372","DOIUrl":"10.1016/j.seminoncol.2025.152372","url":null,"abstract":"<div><div>Glioblastoma (GBM) continues to be 1 of the most malignant tumors with limited success in therapy, primarily owing to the emergence of resistance towards temozolomide TMZ. Resistance to TMZ is a multifactorial phenomenon in GBM, depending on the interactions between genetic, epigenetic, and microenvironmental factors. Noncoding RNAs, most significantly circRNAs, have recently been highlighted as playing important roles in the pathogenesis of GBM and drug resistance against TMZ. These stable, circular RNA molecules can act as microRNA sponges or encode functional peptides; hence, they modulate functions relating to different aspects of tumor development. Furthermore, circRNAs can be carried within exosomes, promoting intercellular communication and propagation of drug resistance. Exosomes serve as sophisticated delivery vehicles that harbor varying bioactive molecules like proteins, lipids, mRNAs, miRNAs, lncRNAs, and many others, including circular RNAs. This review elucidates the specific functions held by exosomal circRNAs, such as circASAP1 and circ-HIPK3, in the modulation of TMZ resistance through different molecular pathways. It also reflects the biomarker potential of exosomal circRNAs as diagnostics and prognostics, allowing their dynamic application in liquid biopsies to monitor the progression of GBM over time. This review tries to develop an understanding of the complex nature of mechanisms conferring resistance to TMZ, with a particular focus on new insights regarding the potential roles of exosomal circular RNAs.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152372"},"PeriodicalIF":3.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144313673","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":"A 3-miRNA signature for noninvasive breast cancer detection","authors":"Amir Ebrahimi ,&nbsp;Davood Ghavi ,&nbsp;Zohreh Mirzaei ,&nbsp;Tahereh Barati ,&nbsp;Mahmood Shekari-Khaniani ,&nbsp;Hossein Gahramani-almangadim ,&nbsp;Sima Mansoori-Derakhshan","doi":"10.1016/j.seminoncol.2025.152363","DOIUrl":"10.1016/j.seminoncol.2025.152363","url":null,"abstract":"<div><div>As a key component of epigenetics, microRNAs (miRNAs) have provided promising insights into several aspects of Breast Cancer (BC). We have analyzed 2 BC tissue microarray datasets (GSE26659 and GSE40525), as well as 2 serum datasets (GSE106817 and GSE113486). The results were then intersected to identify commonly dysregulated miRNAs in the tissue and serum of BC patients. RNA-seq analysis was then applied to The Cancer Genome Atlas (TCGA) data. Briefly, 79 dysregulated miRNAs were identified in the tissue and serum of patients with BC of which 3 significantly dysregulated and previously unstudied miRNAs, let-7e-5p, miR-151a-5p and miR-887-3p, were chosen for quantification in the serum of cancer patients by RT-PCR followed by evaluation of their diagnostic and prognostic features. RT-PCR analysis revealed overexpression of let-7e-5p (logFC = 2.01, <em>P</em> &lt; .05) and miR-151a-5p (logFC = 1.48, <em>P</em> &lt; .05) whereas miR-887-3p was downregulated (logFC = 0.62, <em>P</em> &lt; .05) similar to microarray and RNA-seq data analysis. Based on regression analysis, a 3 miRNA-signature biomarker was proposed which had better diagnostic ability (AUC = 84.17%) compared to the ability of these miRNAs when assessed individually. Moreover, enrichment analysis revealed these miRNAs mediate vital cellular processes and biological functions that influence the development of cancer. Similarly, significant prognostic clinical characteristics were observed for these miRNAs. Overall, we have identified and validated a novel and proficient signature biomarker in serum of BC patients consisting of 3 miRNAs.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152363"},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144263216","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":"Identifying and closing information gaps in head and neck cancer surgery","authors":"Sabrina R Comess BA ,&nbsp;Justin K Joseph BA ,&nbsp;Michelle Yoon BA ,&nbsp;Salmaan Sayeed BS ,&nbsp;Pranati Borkhetaria BA ,&nbsp;Luke Stanisce MD ,&nbsp;Margaret Brandwein-Weber MD ,&nbsp;Michael Karasick PhD ,&nbsp;Mark L Urken MD","doi":"10.1016/j.seminoncol.2025.152362","DOIUrl":"10.1016/j.seminoncol.2025.152362","url":null,"abstract":"<div><div>Contemporary cancer management relies on the precise transfer of information regarding disease and treatment details between a range of providers and facilities. The time of surgery is uniquely responsible for many ambiguities in this oncological information flow, as intraoperative communication and documentation are often unregimented and imprecise. Downstream providers such as radiation oncologists, medical oncologists, and radiologists rely on surgical pathology reports for planning postoperative treatment and surveillance. However, traditional pathology reports lack critical details about the actions taken during surgery and do not make the oncologic clearance status explicit. We identified agents of change to improve information transfer and designed an improved surgical workflow and pathology report that make use of a novel pathologic reporting software to address gaps in the oncologic care timeline. Our updated workflow results in a dynamic final pathology report that integrates annotated 3D scans of the surgical specimen and extirpative defect, unequivocal reconciliation of at-risk and supplemental margins, highlighted preoperative radiographs, and brief narrative summaries by the surgeon and pathologist. These tangible changes aim to improve clarity and continuity in oncologic care.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152362"},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254034","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":"Advancing personalized medicine in LMICs: Predictive indicators for cervical cancer immunotherapy response","authors":"Carla Eksteen ,&nbsp;Johann Riedemann ,&nbsp;Frederick H. van der Merwe ,&nbsp;Matthys H. Botha ,&nbsp;Anna-Mart Engelbrecht","doi":"10.1016/j.seminoncol.2025.152352","DOIUrl":"10.1016/j.seminoncol.2025.152352","url":null,"abstract":"<div><div>The World Health Organization reports that cervical cancer ranks as the eighth most common cancer worldwide and is the ninth leading cause of cancer-related deaths. It is also the most prevalent cancer among women in 25 countries, primarily in Sub-Saharan Africa. Consequently, cervical cancer continues to pose a significant global health challenge, particularly due to the limited treatment options available for advanced stages of the disease. Evidently, immunotherapy is a promising strategy, but its efficacy is variable among patients. As such, predictive indicators are essential for identifying patients who are most likely to benefit from immunotherapy and for guiding treatment decisions. This review provides an overview of the current landscape of predictive biomarkers in cervical cancer immunotherapy, including immune checkpoint molecules, tumor mutational burden and immune cell infiltration. We further discuss additional factors such as cytokines, tumor infiltrating lymphocytes and previous exposure to platinum-based chemotherapy. As the field continues to evolve, ongoing research efforts are needed to refine predictive biomarkers and optimize patient selection in LMICs for immunotherapy in cervical cancer.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152352"},"PeriodicalIF":3.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144254699","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":"Atezolizumab plus bevacizumab versus Lenvatinib for patients with Barcelona clinic liver cancer stage B (BCLC-B) hepatocellular carcinoma (HCC): A real-world population","authors":"Francesco Vitiello ,&nbsp;Toshifumi Tada ,&nbsp;Goki Suda ,&nbsp;Shigeo Shimose ,&nbsp;Masatoshi Kudo ,&nbsp;Jaekyung Cheon ,&nbsp;Fabian Finkelmeier ,&nbsp;Ho Yeong Lim ,&nbsp;José Presa ,&nbsp;Gianluca Masi ,&nbsp;Changhoon Yoo ,&nbsp;Sara Lonardi ,&nbsp;Francesco Tovoli ,&nbsp;Takashi Kumada ,&nbsp;Mario Scartozzi ,&nbsp;Emiliano Tamburini ,&nbsp;Francesco Giuseppe Foschi ,&nbsp;Mara Persano ,&nbsp;Federico Rossari ,&nbsp;Silvia Foti ,&nbsp;Margherita Rimini","doi":"10.1016/j.seminoncol.2025.152348","DOIUrl":"10.1016/j.seminoncol.2025.152348","url":null,"abstract":"<div><h3>Background</h3><div>The aim of the present study was to perform a real-world analysis on a large patient cohort with Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (<em>A</em> + <em>B</em>) or with Lenvatinib.</div></div><div><h3>Methods</h3><div>The study population included patients affected with Barcelona Clinic Liver Cancer stage B (BCLC-B) hepatocellular carcinoma not suitable for locoregional therapies (LRTs) from eastern and western populations, who received atezolizumab plus bevacizumab (<em>A</em> + <em>B</em>) or Lenvatinib as first-line treatment. Univariate and multivariate analyses were used to evaluate predictive factors for overall survival (OS) and time to progression (TTP) while prognostic factors were analyzed by univariate and multivariate analysis using Cox regression model.</div></div><div><h3>Results</h3><div>919 patients with BCLC-B HCC were analyzed in the study. Lenvatinib was administered to 561 (61%) patients while 358 (39%) received <em>A</em> + <em>B</em>. The median overall survival (mOS) for patients receiving Lenvatinib was 21.3 months compared to 15.8 months for patients receiving <em>A</em> + <em>B</em> as first-line treatment (Lenvatinib <em>v A</em> + <em>B</em>), hazard ratio (HRs) 0.84 <em>P</em> = 0.22. The median time to progression (mTTP) for patients receiving Lenvatinib was 7.3 months compared to 8.7 months for patients receiving <em>A</em> + <em>B</em> as first-line treatment (Lenvatinib <em>v A</em> + <em>B</em>): HR 1.15 <em>P</em> = 0.10. Multivariate analysis confirmed no different in terms of mOS and mTTP between the two treatments. Objective response rate (ORR) was 47.1% for patients receiving Lenvatinib and 27.1% for patients receiving <em>A</em> + <em>B P</em> &lt; 0.000001. Patients receiving Lenvatinib experienced a significantly higher incidence of hand-foot skin reaction (HFSR), hypertension, diarrhea, fatigue, decrease appetite, hypothyroidism, and other toxicity compared to patients receiving <em>A</em> + <em>B</em>. Favorable prognostic factors for OS in Lenvatinib group were platelets (PLT) &gt;100.000 (HR 0.68 <em>P</em> = 0.02), HCC nonalcoholic steatohepatitis/nonalcoholic fatty liver disease (NASH/NAFLD) related (HR 0.53, <em>P</em> = 0.03). No favorable prognostic factors were found for <em>A</em> + <em>B</em> group. Favorable prognostic factors for TTP in the <em>A</em> + <em>B</em> group were in TACE refractory patients (HR 0.76, <em>P</em> = 0.02), PLT &lt;100.000 (HR 0.62, <em>P</em> = 0.0067), and neutrophil-to-lymphocyte ratio (NLR) &lt; 3 (HR 0.78, <em>P</em> = 0.04).</div></div><div><h3>Conclusion</h3><div>Although Lenvatinib had a higher response rate, the study showed no statistically significant differences between Lenvatinib and <em>A</em> + <em>B</em> in terms of efficacy, in patients with BCLC-B HCC.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152348"},"PeriodicalIF":3.0,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144240330","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":"CTLA-4 blockade in ovarian cancer immunotherapy: Mechanisms and clinical strategies","authors":"Chou-Yi Hsu ,&nbsp;Thikra Majid Muhammed ,&nbsp;Subasini Uthirapathy ,&nbsp;Irfan Ahmad ,&nbsp;Suhas Ballal ,&nbsp;Rishiv Kalia ,&nbsp;Premkumar J ,&nbsp;Subhashree Ray ,&nbsp;Riyadh Mohammed Mohsin ,&nbsp;Abid ALi A. Abiess","doi":"10.1016/j.seminoncol.2025.152370","DOIUrl":"10.1016/j.seminoncol.2025.152370","url":null,"abstract":"<div><div>Although studies have demonstrated that ovarian cancer cells can express immune checkpoint proteins like CTLA-4 and that higher levels of tumor-infiltrating lymphocytes are linked to better patient survival, clinical trials utilizing immune checkpoint inhibitors in ovarian cancer have not yielded encouraging results. Tumor heterogeneity and innate or acquired resistance associated with the tumor microenvironment (TME) may account for the inadequate response to ICIs. Understanding tumor immunobiology, identifying biomarkers for patient selection, and formulating suitable treatment regimens remain challenging, yet these are the aspirations for the future use of immunotherapy in ovarian cancer. Induced T cells express CD80 and CD86, providing a positive costimulatory signal via CD28. CTLA-4 antagonizes CD28, diminishing T cell activation and modulating the immunological response. Conversely, the negative regulation of CTLA-4 using monoclonal antibodies (mAbs), particularly ipilimumab, may stimulate T-cell responses against ovarian cancer antigens. We elucidate the mechanisms responsible for immunological suppression: T cell exhaustion and senescence in ovarian cancer. We also provide a synopsis of using CTLA-4 monoclonal antibodies in ovarian cancer alone or conjunction with other modalities (eg, chemotherapy). We finally delineate the challenges associated with responding to immunotherapy in ovarian cancer.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152370"},"PeriodicalIF":3.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144221495","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":"Hexokinases in gastrointestinal cancers: From molecular insights to therapeutic opportunities","authors":"Guodong Liang ,&nbsp;Yuehan Ma ,&nbsp;Ping Deng ,&nbsp;Shufeng Li ,&nbsp;Chunyan He ,&nbsp;Haihang He ,&nbsp;Hairui Liu ,&nbsp;Yunda Fan ,&nbsp;Ze Li","doi":"10.1016/j.seminoncol.2025.152351","DOIUrl":"10.1016/j.seminoncol.2025.152351","url":null,"abstract":"<div><div>Hexokinases (HKs) catalyze the first step in glycolysis by transferring a phosphate group to glucose to produce glucose-6-phosphate (G6P); dysregulation of HKs is a feature that leads to altered metabolism within gastrointestinal (GI) cancers—namely, gastric, colorectal, esophageal, and pancreatic cancer. Of note, HKs have been found to exert non-canonical roles beyond metabolism, particularly in regulating cell death pathways such as autophagy and apoptosis in these cancers. In this sense, HK2 promotes hepatocellular carcinoma (HCC) from apoptosis inhibition through the suppression of mitochondrial permeability transition pore formation by interaction with voltage-dependent anion channel (VDAC). Moreover, HK2 expression in HCC tumors decreases immune responsiveness and sensitivity to natural killer (NK) cytotoxicity, thus favoring immune escape. HK2 and co-expressed genes participate in esophageal cancer (ESCA) microenvironment immune response, especially in B cells, CD4 T cells, and macrophages. Most importantly, 3-BP, an HK-2 inhibitor, induces endoplasmic reticulum (ER) stress and disruption of the ER function by the accumulation of free radicals or reactive oxygen species (ROS) and the protein misfolding, thereby causing apoptosis in human HCC. Of note, it has been found that interaction of HK domain containing protein-1 (HKDC1) with ACTA2 (actin alpha 2) is required for the association of signal transducer and activator of transcription 1 (STAT1) with interferon-gamma receptor (IFNG-R) on the plasma membrane, STAT1-phosphorylation, and thus programmed cell death ligand 1 (PD-L1) expression upon stimulation with IFNγ in HCC. This review summarizes the mechanistic involvement of HKs in glycolytic reprogramming, apoptotic resistance, autophagy, immune evasion, metastasis, and drug resistance in GI cancers and the potential of HKs as diagnostic and therapeutic targets.</div></div>","PeriodicalId":21750,"journal":{"name":"Seminars in oncology","volume":"52 4","pages":"Article 152351"},"PeriodicalIF":3.0,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144212884","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}