Journal of Experimental & Clinical Cancer Research最新文献

{"title":"Vinburnine potentiates anti-PD1 immunotherapy in melanoma through IL-24 secretion via P38/MAPK/ATF3 signaling.","authors":"Susi Zhu, Xu Zhang, Waner Liu, Zhe Zhou, Siyu Xiong, Xiang Chen, Cong Peng","doi":"10.1186/s13046-025-03521-5","DOIUrl":"https://doi.org/10.1186/s13046-025-03521-5","url":null,"abstract":"<p><strong>Background: </strong>Melanoma, a highly aggressive and immunogenic skin cancer, often develops resistance to immunotherapy due to the immunosuppressive tumor microenvironment (TME). Although PD-1/PD-L1 inhibitors have significantly improved treatment outcomes, 30%-40% of patients exhibit no response or develop resistance. Mechanisms such as T-cell exhaustion within the TME limit therapeutic efficacy, necessitating the exploration of novel strategies to enhance immune responses.</p><p><strong>Methods: </strong>This study evaluated the effects of Vinburnine (Vin) on melanoma cell proliferation, migration, invasion, apoptosis, and DNA damage through in vitro experiments. Transcriptomic analysis, Western blot, RT-PCR, dual-luciferase reporter assays, and ChIP experiments revealed the mechanism by which Vin regulates IL-24 via ATF3. The anti-tumor efficacy of Vin or IL-24 in combination with PD-1 monoclonal antibody, as well as their modulation of the tumor microenvironment, were validated through luciferase-mediated cytotoxicity assays and a murine melanoma model. Additionally, the correlation between IL-24 expression and patient prognosis or immunotherapy response was analyzed using public databases.</p><p><strong>Results: </strong>This study delineates the phenotypic mechanisms by which vinburnine suppresses melanoma proliferation. Vin induces reactive oxygen species (ROS) generation, leading to DNA damage and the subsequent activation of the apoptotic cascade in melanoma cells. Additionally, vinburnine activates the P38/MAPK/ATF3 signaling axis, which drives the secretion of interleukin-24 (IL-24), enhancing the functionality of CD8⁺ T cells and modulating the tumor immune microenvironment to favor antitumor immunity. Notably, the combination of vinburnine with anti-PD-1 antibody therapy produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches.</p><p><strong>Conclusions: </strong>These findings underscore the therapeutic potential of vinburnine, particularly when used in combination with immune checkpoint inhibitors, as a promising strategy for melanoma treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"255"},"PeriodicalIF":12.8,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional tumor-reactive CD8 + T cells in pancreatic cancer.","authors":"Hongwei Sun, Changying Shi, Guoqing Fang, Qiufang Guo, Zhengliang Du, Geer Chen, Yasong Wu, Zhe-Sheng Chen, Jian Hua, Yan Zhang, Zhiwen Shi","doi":"10.1186/s13046-025-03517-1","DOIUrl":"https://doi.org/10.1186/s13046-025-03517-1","url":null,"abstract":"<p><strong>Background: </strong>Traditional methods for detecting tumor-reactive (TR) CD8 + tumor-infiltrating lymphocytes (TILs) in pancreatic cancer usually focus on neo-antigenic epitopes, which is limited by the narrow range of antigenic epitopes, and the lengthy and complex identification processes, resulting in an incomplete understanding of the biological characteristics of TR CD8 + TILs.</p><p><strong>Methods: </strong>This study introduces a novel approach that integrates single-cell sequencing with deep learning (DL), which enables the identification of tumor-reactive CD8 + T cells without neoantigen screening. The T Cell Receptor Engineered T (TCR-T) cell tumor organoid killing model was employed to validate the functionality of DL-identified TR CD8 + T cells, while spatial transcriptomics was used to confirm receptor-ligand interactions involving TR CD8 + TILs.</p><p><strong>Results: </strong>Comprehensive analyses of TR CD8 + TILs revealed impaired mitochondrial respiratory chain-related pathways regulated by the transcription factor FOS. The TIGIT-NECTIN2 axis was identified as an important immune checkpoint molecule in the tumor microenvironment of pancreatic cancer. T cell receptor (TCR) repertoire analysis demonstrated that some TR CD8 + TILs possess multiple TCR αβ combinations. Furthermore, TCR-T targeting experiments using tumor organoids revealed that combinations of multiple distinct TR TCRs exhibit significantly superior tumor-killing capabilities compared to a single type TCR. Clinically, a higher proportion of TR CD8 + TILs was positively associated with improved responses to neoadjuvant immunotherapy and longer overall survival in pancreatic cancer patients.</p><p><strong>Conclusion: </strong>This study represents a significant advancement in the understanding of TR TIL biology and provides a rapid and accurate method to identify TR CD8 TILs.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"253"},"PeriodicalIF":12.8,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12379552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy resistance in non-small cell lung cancer: from mechanisms to therapeutic opportunities.","authors":"Huiyu Wang, Xiaomin Niu, Zhenning Jin, Shaoxing Zhang, Rong Fan, Hua Xiao, Shen S Hu","doi":"10.1186/s13046-025-03519-z","DOIUrl":"https://doi.org/10.1186/s13046-025-03519-z","url":null,"abstract":"<p><p>This review provides a comprehensive synthesis of current knowledge on immunotherapy resistance in non-small cell lung cancer (NSCLC), a disease that accounts for approximately 85% of all lung cancer cases and remains the leading cause of cancer-related death worldwide. Although immune checkpoint inhibitors (ICIs) have significantly improved survival for a subset of patients with advanced NSCLC, over 70% of cases ultimately exhibit primary or acquired resistance, underscoring the urgent need to understand the underlying mechanisms. The review categorizes resistance into tumor-intrinsic and tumor-extrinsic processes and provides an in-depth mechanistic analysis of how factors such as tumor antigen loss, impaired antigen presentation, cGAS-STING pathway dysregulation, metabolic reprogramming in tumor microenvironment (TME), immune cell exhaustion, and microbiomes collectively contribute to immune escape. In parallel, the influence of the lung and gut microbiome on shaping immunotherapy responses is discussed, with emphasis on microbial dysbiosis, immunosuppressive metabolite production, and TME remodeling. Therapeutic strategies to overcome resistance are also discussed, including combination approaches involving chemotherapy, radiotherapy, and antiangiogenic agents, as well as epigenetic modulators (HDAC and BET inhibitors). Moreover, the review explores bispecific antibodies, antibody-drug conjugates, and small-molecule agents that enhance T cell function or disrupt immunosuppressive signaling networks. By integrating insights from preclinical models and clinical trials, the review underscores the necessity of biomarker-guided patient stratification, combination immunotherapy approaches, and interventions that restore tumor immunogenicity. It concludes that a multipronged therapeutic strategy, one that addresses both immune evasion and TME-induced suppression, holds the greatest promise for improving response durability and advancing personalized immunotherapy for NSCLC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"250"},"PeriodicalIF":12.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374485/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unleashing NK cells for cancer immunotherapy in lung cancer: biologic challenges and clinical advances.","authors":"Quinlan McLaughlin, Dorothy K Sojka, Kathleen Kennedy, Sytse J Piersma, Nan Sethakorn","doi":"10.1186/s13046-025-03503-7","DOIUrl":"https://doi.org/10.1186/s13046-025-03503-7","url":null,"abstract":"<p><p>Natural killer (NK) cells are a crucial part of the innate immune system and serve as an important effector for killing tumor cells through direct cytolytic activity or immunomodulatory signaling to T cells and antigen presenting cells. NK cells are correlated with increased tumor control and better overall patient survival across various types of cancers including non-small cell lung cancer (NSCLC). Despite their promising potential for anti-tumor killing, NK cell function is often diminished within the tumor microenvironment. There are many factors that lead to decreased tumor-infiltrating NK cell killing, including immunoinhibitory factors from tumor cells and resident tissues, acquired immune tolerance, NK cell exhaustion, and the hypoxic state of the tumor microenvironment. Unleashing NK cell activity therefore has high potential to create a new class of immunotherapy that could combat both primary and acquired resistance to current checkpoint inhibitors. In this review we discuss mechanistic details of NK cell tumor killing, NK cell immunosuppression, and gaps in knowledge regarding highly complex microenvironment-specific effects on NK cell function. We also discuss the promise and limitations of emerging NK-cell based therapeutic strategies.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"251"},"PeriodicalIF":12.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H4K79 and H4K91 histone lactylation, newly identified lactylation sites enriched in breast cancer.","authors":"Jiena Liu, Liuying Zhao, Meisi Yan, Shengye Jin, Lingmin Shang, Jianyu Wang, Qin Wang, Shilu Zhao, Zibo Shen, Tong Liu, Hao Wu, Da Pang","doi":"10.1186/s13046-025-03512-6","DOIUrl":"https://doi.org/10.1186/s13046-025-03512-6","url":null,"abstract":"<p><p>Metabolic reprogramming and epigenetic modification are two hallmarks of cancer. Protein lysine lactylation (Kla) is a novel type of glycolysis lactate-triggered posttranslational modification. However, the role of Kla in breast cancer (BC) remains largely unknown. Here, western blot, and immunohistochemical (IHC) staining of BC tissues revealed that global Kla levels were upregulated in BC tissues, and high levels of Kla were correlated with poor prognosis of patients with BC. A series of in vitro and in vivo assays demonstrated that interruption of glycolysis by lactate dehydrogenase (LDH) inhibitor or silencing LDHA and LDHB repressed the malignant behaviors of BC cells. Moreover, 4D label-free quantitative lactylproteomics analysis of BC tissues and cells revealed that lactylated proteins widely existed in several subcellular compartments and were closely associated with various cancer-related biological processes. Notably, two previously unresearched sites of histone lactylation, H4K79 lactylation (H4K79la) and H4K91 lactylation (H4K91la), were identified to be hyperlactylated in cancer tissues and cells. Glycolytic genes, such as lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), and hexokinase 1 (HK1) were identified to be the potential candidate genes epigenetically regulated by H4K79la and H4K91la by intersecting through chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing (RNA-seq), and TCGA-BRCA database. Pharmacological inhibition of glycolysis downregulated H4K79 and H4K91 lactylation and suppressed the expression of glycolytic genes, whereas treatment with sodium lactate exhibited the opposite effects. Additionally, E1A-binding protein p300 (P300) acted as lysine lactyltransferase to regulate H4K79la and H4K91la, and control the transcription and expression of downstream glycolytic genes in BC cells. The results revealed an intriguing positive feedback loop formed by glycolysis/H4K79la/H4K91la/glycolytic genes in BC, highlighting the relationship between metabolic reprogramming and epigenetic regulation. These findings provide new therapeutic targets for patients with BC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"252"},"PeriodicalIF":12.8,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374308/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"B7-H3 and CSPG4-targeted CAR T cells as potent effectors in anaplastic thyroid cancer.","authors":"Giulia Cattaneo, Marco Ventin, Shahrzad Arya, Cedric Bailey, Venkata Rao Vantaku, Jingyu Jia, Maoyang Qi, Luke Maggs, Xinhui Wang, Sareh Parangi, Soldano Ferrone, Cristina R Ferrone","doi":"10.1186/s13046-025-03475-8","DOIUrl":"https://doi.org/10.1186/s13046-025-03475-8","url":null,"abstract":"<p><strong>Background: </strong>Anaplastic thyroid cancer (ATC) is a rare and aggressive malignancy with poor survival and no available effective therapy. This unmet clinical need led us to investigate chimeric antigen receptor (CAR) T cells s as potential treatment option for this malignant disease. As target tumor antigens of our CAR T cell therapy, we selected the chondroitin sulfate proteoglycan 4 (CSPG4) and the B7-homolog 3 (B7-H3), as they are both highly and homogeneously expressed on different types of thyroid carcinoma cell lines and tissues, including ATC. Importantly, both CSPG4 and B7-H3 have a low distribution on normal tissues, thus limiting 'on-target off-tumor' CAR T-related toxicities.</p><p><strong>Methods: </strong>We generated CSPG4-specific and B7-H3-specific CAR T cells by utilizing a second-generation CAR construct comprised of a CD28 costimulatory domain and tested their antitumor activity in vitro and in an orthotopic xenograft murine model of ATC.</p><p><strong>Results: </strong>We demonstrated that thyroid cancer cells are specifically recognized and effectively eradicated in vitro by CSPG4-targeted and B7-H3-targeted CAR T cells. Additionally, both CAR T cell types were able to mediate significant control or complete eradication of primary ATC tumors when mice were treated with CSPG4 CAR T cells or B7-H3 CAR T cells, respectively.</p><p><strong>Conclusion: </strong>Overall, in this study we identified CSPG4 and B7-H3 as valuable target antigens in thyroid cancer and demonstrated that CAR T cell immunotherapy can be a valuable therapeutic option for ATC patients. Our findings provide the translational basis for exploring CAR T cell immunotherapies targeting CSPG4 and B7-H3 with ATC patients who do not respond or relapse after first line treatment.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"248"},"PeriodicalIF":12.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic profiling identifies a stromal TGF-β1/podoplanin axis as a driver of colorectal cancer progression.","authors":"Silvia Di Agostino, Davide La Padula, Vittoria Rago, Caterina Gabriele, Francesco Conforti, Elio Aprigliano, Lidia Urlandini, Elvira Parrotta, Danilo Lofaro, Francesca Vescio, Andrea Sacconi, Valeria Cernaro, Giuseppe Currò, Angela Alibrandi, Girolamo Ranieri, Valeria Zuccalà, Antonio Ieni, Marco Gaspari, Giovanni Cuda, Michele Ammendola, Vittorio Abbonante","doi":"10.1186/s13046-025-03496-3","DOIUrl":"https://doi.org/10.1186/s13046-025-03496-3","url":null,"abstract":"<p><strong>Background: </strong>The tumor microenvironment (TME) plays a pivotal role in the development and progression of colorectal cancer (CRC), yet the complex crosstalk among its components remains incompletely understood. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) have emerged as key regulators of CRC progression, but their specific contributions, particularly given their heterogeneity, are not fully elucidated. This study identifies podoplanin (PDPN), a transmembrane glycoprotein enriched in CAFs, as highly expressed in the CRC TME, in particular surrounding the tumor, and associated with macrophage infiltration and cancer progression.</p><p><strong>Methods: </strong>We performed mass spectrometry-based proteomic analysis on matched CRC and adjacent normal tissues from patients to identify altered signaling pathways and protein expression. The clinical relevance of PDPN expression was evaluated in CRC samples from two independent cohorts using immunohistochemistry and immunofluorescence analysis. Publicly available data from the Gene Expression Omnibus (GEO) database were analyzed to assess the association between PDPN expression and patient survival. Functional assays using direct and indirect co-culture systems investigated the influence of macrophage infiltration on stromal PDPN expression and its effect on colon adenocarcinoma cell growth.</p><p><strong>Results: </strong>PDPN expression was significantly elevated in the stroma of the colorectal tumor tissues compared to normal tissues and correlated with M2-like macrophage infiltration. High PDPN expression was associated with reduced relapse-free survival in CRC patients. Stromal cells pre-conditioned with M2-like macrophages upregulated PDPN and more effectively supported the growth of three colon adenocarcinoma cell lines. PDPN depletion impaired the ability of stromal cells to promote tumor cell proliferation. Mechanistically, M2-like macrophage pre-conditioning induced a TGF-β1-dependent increase in YAP/TAZ nuclear localization, RhoA/ROCK/myosin-driven cytoskeletal contractility, and extracellular matrix (ECM) production in stromal cells. Inhibition of TGF-β1 signaling or ROCK activity reduced stromal support for cancer cell growth.</p><p><strong>Conclusion: </strong>This study reveals a novel mechanism by which the TME facilitates CRC progression and highlights PDPN as a potential prognostic biomarker and therapeutic target in CRC.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"247"},"PeriodicalIF":12.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the interplay of cGAS-STING and ferroptosis by nanomedicine in the treatment of cancer.","authors":"Chunfei Li, Wenyan Zhao, Donghua Geng, Yuzi Jin, Wenzheng Guan","doi":"10.1186/s13046-025-03520-6","DOIUrl":"https://doi.org/10.1186/s13046-025-03520-6","url":null,"abstract":"<p><p>The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway senses cytosolic DNA and triggers innate immune responses. Pharmacological activation of the cGAS-STING pathway by cGAS-STING agonists to overcome cancer drug resistance offers substantial potential to promote antitumor immunity. However, small-molecule STING agonists show rapid excretion, low bioavailability, non-specificity, and adverse effects, which limit their therapeutic efficacy and in vivo applications. The recent emergence of nanomedicine has profoundly revolutionized STING agonist delivery, promoting tumor-targeted delivery and offering new opportunities for tumor-specific immunotherapy. A growing body of evidence has shown that cGAS-STING interacts with ferroptosis in cancer cells. Targeting the interplay between cGAS-STING and ferroptosis using nanomedicines offers a novel cancer treatment regimen. In this review, we outline the principal components of the cGAS-STING signaling cascade and discuss its role in cancer biology. We also review the role of the interplay between cGAS-STING and ferroptosis in cancer genesis. We then focus on providing an overview of the latest findings and emerging concepts that leverage the interplay between cGAS-STING and ferroptosis by nanomedicine to kill cancers. Finally, we discuss the key limitations of the current therapeutic paradigm and possible strategies to overcome them. This article highlights some promising therapeutic avenues that leverage the interplay of cGAS-STING and ferroptosis by nanomedicine, which could be used to treat cancer.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"249"},"PeriodicalIF":12.8,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372235/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144976139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new era in cancer therapy: targeting the Proteasome-Bcl-2 axis.","authors":"Sourabh Soni, Vandana Anang, Yutong Zhao, Jeffrey C Horowitz, Richard S Nho, Yohannes A Mebratu","doi":"10.1186/s13046-025-03505-5","DOIUrl":"https://doi.org/10.1186/s13046-025-03505-5","url":null,"abstract":"<p><p>The B-cell lymphoma-2 (Bcl-2) family proteins, key regulators of apoptosis, are frequently dysregulated in cancer, tipping the balance of cell survival and apoptosis in favor of survival. The ubiquitin-proteasome system (UPS) is a critical cellular machinery that controls the Bcl-2 levels through regulation of protein stability. This review delves into the intricate interplay between the proteasome and Bcl-2 family members, exploring how proteasome-mediated degradation impacts cell survival and proliferation to influence cancer progression. We discuss the therapeutic potential of targeting the proteasome-Bcl-2 axis, including the use of proteasome inhibitors as anticancer agents. We examine their mechanisms of action, clinical efficacy, and limitations while exploring emerging strategies to overcome these challenges.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"246"},"PeriodicalIF":12.8,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144977140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyrotinib targeted EGFR/GRP78 mediated cell apoptosis in high EGFR gene copy number gastric cancer.","authors":"Lingbo Bao, Xudong Wang, Xiuyong Liao, Dong Li, ChunXue Li, Nan Dai, Xiaoyan Dai, Jing Yang, Nana Hu, Xueling Tong, Zhenjie He, Yuancheng Zhao, Zheng Liu, Yue Hu, Jinlu Shan, Dong Wang, Mengxia Li, Qian Chen","doi":"10.1186/s13046-025-03485-6","DOIUrl":"10.1186/s13046-025-03485-6","url":null,"abstract":"<p><strong>Background: </strong>Despite frequent Epidermal Growth Factor Receptor (EGFR) amplification and overexpression in gastric cancer, limited therapeutic responses were observed in existing EGFR-targeted agents. Pyrotinib, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor, has shown clinical efficacy in HER2-driven malignancies, but its potential role in EGFR-high copy number gastric cancer remains to be investigated.</p><p><strong>Methods: </strong>Using EGFR-high copy number gastric cancer cell lines, primary cells and subcutaneous tumor models in nude mice, we systematically evaluated pyrotinib's anti-tumor activity through viability assays, apoptosis analysis, and transcriptomic profiling. Mechanistic studies included co-immunoprecipitation, proximity ligation assays, ubiquitination assays, and RNA sequencing.</p><p><strong>Results: </strong>Pyrotinib selectively suppressed proliferation, induced apoptosis, and chemosensitized in EGFR-high copy number gastric cancer models. Mechanistically, pyrotinib promoted EGFR-GRP78 (Glucose-regulated protein 78) complex formation in the endoplasmic reticulum, activating the protein kinase R-like endoplasmic reticulum kinase/ activating transcription factor 4/ C-EBP homologous protein (PERK/ATF4/CHOP) axis to drive ER stress-mediated apoptosis. Concurrently, pyrotinib inhibited GRP78 phosphorylation at Thr62, triggering K48-linked ubiquitination (ubiquitin chains formed via lysine 48 linkages) and proteasomal degradation, which impaired DNA double-strand break (DSB) repair and sensitized cells to oxaliplatin-induced γ-H2A.X accumulation.</p><p><strong>Conclusion: </strong>This translational study suggests that pyrotinib combined with oxaliplatin may serve as a promising strategy for patients with EGFR-high copy number gastric cancer and highlighted the discovery of this previously unknown EGFR/ GRP78 signaling axis, which provides the molecular basis and the rationale to target EGFR.</p>","PeriodicalId":50199,"journal":{"name":"Journal of Experimental & Clinical Cancer Research","volume":"44 1","pages":"245"},"PeriodicalIF":12.8,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363034/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144884204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}