Drug Resistance Updates最新文献

{"title":"RCN2 facilitates esophageal squamous cellular carcinoma metastasis and cisplatin resistance through UBR5-mediated PPP2CA ubiquitination and degradation","authors":"Mengyuan Wu ,&nbsp;Xu Huang ,&nbsp;Miao Lin ,&nbsp;Zhiyun Duan ,&nbsp;Zitao Jian ,&nbsp;Runze You ,&nbsp;Peiyi Xie ,&nbsp;Zhiwei Wu ,&nbsp;Siyun Lin ,&nbsp;Shaoyuan Zhang ,&nbsp;Wenyi Xu ,&nbsp;Heng Jiao ,&nbsp;Han Tang ,&nbsp;Lei Guo ,&nbsp;Hao Wang ,&nbsp;Weigang Guo ,&nbsp;Lijie Tan","doi":"10.1016/j.drup.2025.101339","DOIUrl":"10.1016/j.drup.2025.101339","url":null,"abstract":"<div><h3>Aims</h3><div>Metastatic progression and treatment resistance determine poor prognostic outcomes of patients with esophageal squamous cellular carcinoma (ESCC), highlighting the urgent need to understand the molecular mechanisms behind this. Reticulocalbin 2 (RCN2) is a calcium-binding protein localized in the endoplasmic reticulum lumen, which mediates tumor progression in various cancer types. However, the role of RCN2 in ESCC remains unexplored.</div></div><div><h3>Methods</h3><div>The influence of RCN2 on ESCC progression, metastasis, and cisplatin (CDDP) resistance was assessed both <em>in vitro</em> and <em>in vivo</em>. The downstream regulatory mechanism associated with RCN2 was screened through RNA-seq, TMT 10X mass spectrometry analysis, and LC-MS/MS analysis, which was further validated through Western blot, immunoprecipitation, immunofluorescence, GST pull-down assay, and rescue experiments.</div></div><div><h3>Results</h3><div>We observed high RCN2 expression in ESCC tumor tissues from patients with metastasis, which is correlated with a higher risk of metastasis and worse survival. PPP2CA, a catalytic subunit of protein phosphatase 2 A (PP2A), and ubiquitin protein ligase E3 component N-recognin 5 (UBR5) are determined as novel RCN2 functioning interactors. Mechanistically, RCN2 facilitates PPP2CA ubiquitination and degradation dependent on the HECT domain of UBR5, thereby activating the PI3K-AKT signaling pathway. Furthermore, the activated RCN2-PPP2CA-PI3K-AKT axis is validated in clinical specimens of ESCC. Finally, targeted suppression of RCN2 synergized with CDDP treatment to prevent tumor growth and metastasis in subcutaneous and lung metastasis models.</div></div><div><h3>Conclusions</h3><div>Overall, these findings identify RCN2 as a novel driver of ESCC metastasis and CDDP resistance. RCN2 could be a promising treatment target for ESCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101339"},"PeriodicalIF":21.7,"publicationDate":"2025-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145689546","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}

{"title":"UBL3 governs VEGFR inhibitor resistance by activating NOTCH signaling in renal cell carcinoma","authors":"Diaoyi Tan ,&nbsp;Yuzhong Ye ,&nbsp;Daojia Miao ,&nbsp;Chuanyi Zhao ,&nbsp;Songming Wu ,&nbsp;Jian Shi ,&nbsp;Junkai Yang ,&nbsp;Kanglin Fang ,&nbsp;Feiyi Lu ,&nbsp;Qingyang Lv ,&nbsp;Jinshuo Gong ,&nbsp;Hongmei Yang ,&nbsp;Wen Xiao ,&nbsp;Zhiyong Xiong ,&nbsp;Xiaoping Zhang ,&nbsp;Hailong Ruan","doi":"10.1016/j.drup.2025.101332","DOIUrl":"10.1016/j.drup.2025.101332","url":null,"abstract":"<div><h3>Background</h3><div>Targeted therapy is the first-line treatment for patients with metastatic renal cell carcinoma (RCC), with vascular endothelial growth factor receptor inhibitors (VEGFRis) constituting the bulk of regimens used. Although the repertoire of VEGFRis for RCC now spans from sunitinib to cabozantinib, resistance to treatments has emerged as a common and prominent challenge. Thus, identifying novel therapeutic targets has become essential for enhancing the antitumor efficacy of current treatments and inhibiting RCC progression.</div></div><div><h3>Method</h3><div>To investigate the potential mechanisms underlying VEGFRi resistance in RCC, we performed a genome-wide CRISPR/Cas9 library screen under sunitinib and cabozantinib treatment and identified UBL3 as a key driver of VEGFRi resistance in RCC cells. The critical role of UBL3 in promoting VEGFRi resistance was validated using CCK8 assays, flow cytometry, TUNEL assays, and bioinformatics analyses. To elucidate the molecular mechanisms underlying UBL3, we utilized western blotting, RNA sequencing, chromatin immunoprecipitation, small extracellular vesicles (sEVs) isolation, and Astral-DIA proteomics. The contribution of UBL3 to VEGFRi resistance was further confirmed through comprehensive in vitro and in vivo experiments.</div></div><div><h3>Results</h3><div>UBL3 was confirmed to suppress apoptosis and promote VEGFRi resistance through NOTCH signaling activation. Further investigations highlighted the importance of NOTCH signaling in VEGFRi resistance in RCC via the NOTCH-PTEN-AKT and NOTCH-FOS pathways and revealed the mechanisms by which UBL3 activated NOTCH signaling. On the one hand, UBL3 formed complex with NOTCH2 and ADAM17 simultaneously, accelerating ADAM17-mediated cleavage of NOTCH2. On the other hand, UBL3-modified NOTCH2 was sorted into sEVs, which were taken up by recipient cells, activating NOTCH signaling and thereby transmitting VEGFRi resistance. Finally, lipid nanoparticle-mediated delivery of the CRISPR/Cas9 knockout system targeting UBL3 effectively restored the sensitivity of RCC tumors to VEGFRis.</div></div><div><h3>Conclusion</h3><div>This study emphasized the importance of UBL3 in VEGFRi resistance in RCC and proposed that UBL3 activated NOTCH signaling through two distinct pathways, thereby suppressing cancer apoptosis and promoting resistance to VEGFRis. These findings provided a solid scientific foundation and paved the way for the development of novel therapeutic strategies for patients with advanced RCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101332"},"PeriodicalIF":21.7,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657171","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}

{"title":"The implied dysregulated RKIP-hypoxia axis in cancer and immune evasion: Clinical implications","authors":"Ryan McWhorter ,&nbsp;Salem Chouaib ,&nbsp;Benjamin Bonavida","doi":"10.1016/j.drup.2025.101328","DOIUrl":"10.1016/j.drup.2025.101328","url":null,"abstract":"<div><div>The Raf kinase inhibitor protein (RKIP) functions as both a metastasis suppressor and immune enhancer, exerting its influence over several key oncogenic signaling pathways, including the MAPK, NF-κB, and PI3K pathways. Recent studies have highlighted a potential interplay between RKIP and hypoxia-inducible factors (HIFs), particularly in the hypoxic tumor microenvironment (TME). Hypoxia is known to reprogram cellular metabolism, enhance angiogenesis, and facilitate immune escape. Through analysis of cross-talk signaling pathways between RKIP and HIFs, we establish the presence of a dysregulated RKIP-hypoxia axis in cancer. Notably, many cancers simultaneously express low levels of RKIP and high levels of HIFs <img> an expression pattern that strongly correlates with the emergence of immune evasion mechanisms. Herein, we report on the mechanisms by which this dysregulated axis mediates immune evasion. These include the molecular regulations of RKIP and HIFs expressions, and the low expression of RKIP and high expression of HIFs in several cancers. We report on the mechanisms underlying immune evasion by the RKIP-hypoxia axis by examining various factors intimately involved in immune evasion, such as the upregulation of PD-L1, matrix metalloproteinases (MMPs), anti-apoptotic molecules, CD47, and the enhanced frequencies of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophage (TAM) polarization, and decreased antigen presentation. Thus, hypoxia-induced repression of RKIP establishes a feedforward loop that sustains immune evasion and tumor aggressiveness. Therapeutically, we propose that targeting the RKIP-hypoxia axis offers a new strategy to restore immune surveillance and counteract tumor progression. We present various means to target the inhibition of hypoxia as well as the induction of RKIP. Elucidating the molecular crosstalk between RKIP and hypoxic stress responses opens a new paradigm for strategies that enhance the efficacy of immunotherapies and overcome tumor resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101328"},"PeriodicalIF":21.7,"publicationDate":"2025-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613768","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}

{"title":"Lars2-signaling mediates platinum resistance by accumulating cancer stem cell population and suppressing anti-tumor immunity","authors":"Yuqing Wang ,&nbsp;Min Deng ,&nbsp;Haipeng Lei ,&nbsp;Kai Miao ,&nbsp;Xiaodong Shu ,&nbsp;Jianjie Li ,&nbsp;Dongyang Tang ,&nbsp;Yangyang Feng ,&nbsp;Sek Man Su ,&nbsp;Ling Li ,&nbsp;Yanjie Wang ,&nbsp;Heng Sun ,&nbsp;Fangyuan Shao ,&nbsp;Tingting An ,&nbsp;Xiaoling Li ,&nbsp;Fanlin Zhou ,&nbsp;Tingxiu Xiang ,&nbsp;Xiaoling Xu ,&nbsp;Chuxia Deng","doi":"10.1016/j.drup.2025.101330","DOIUrl":"10.1016/j.drup.2025.101330","url":null,"abstract":"<div><div>Platinum-based chemotherapy remains a cornerstone of cancer treatment; however, its clinical efficacy is frequently compromised by acquired drug resistance. Our study elucidated a novel resistance mechanism mediated by LARS2 signaling in mammary tumors. Through comprehensive multi-omics analyses of cancer patients, mouse models, and functional validation, we demonstrated that platinum treatment upregulates LARS2 via a danger-triggered host response during resistant tumor progression, concomitant with increased chromatin accessibility. This signaling drives drug resistance through two key mechanisms: enrichment of cancer stem cells and promotion of TGF-β-mediated immunosuppression, as evidenced by M2 macrophage polarization and CD8⁺ T cell exhaustion. Importantly, we developed an effective therapeutic strategy combining carboplatin with LARS2 signaling pathway inhibition, which successfully reversed platinum resistance and restored PD-1 checkpoint blockade sensitivity in preclinical models. These findings not only advance our understanding of chemotherapy resistance, but also provide a translatable therapeutic framework for breast cancer and other platinum-treated malignancies.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101330"},"PeriodicalIF":21.7,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613764","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}

{"title":"Glucocorticoid receptor activated by dexamethasone promotes the chemoresistance and stemness of lung cancer","authors":"Ting Yu ,&nbsp;Dandan Peng ,&nbsp;Xiao Liang ,&nbsp;Wen Nie ,&nbsp;Huaicheng Tan ,&nbsp;Siyuan Chen ,&nbsp;Huashan Shi ,&nbsp;Yuquan Wei ,&nbsp;Xiawei Wei","doi":"10.1016/j.drup.2025.101331","DOIUrl":"10.1016/j.drup.2025.101331","url":null,"abstract":"<div><h3>Aims</h3><div>Glucocorticoids (GCs) such as dexamethasone are routinely used in patients to alleviate side effects of chemotherapeutic agents or symptoms caused by advanced cancer. However, growing evidences have found glucocorticoids-induced chemoresistance in solid tumors, while the potential effects and underlying mechanisms are still remained unclearly. This study aimed to reveal the underlying mechanism of glucocorticoids-induced chemoresistance in lung cancer.</div></div><div><h3>Methods</h3><div>Effects of dexamethasone on chemotherapy efficiency and stemness properties were tested both <em>in vitro</em> and <em>in vivo</em> assays. Underlying mechanism of dexamethasone was revealed by western blot, protein immunoprecipitation, molecular dynamics simulation, high-resolution mass spectrometry detection and RNA-sequencing. Prognostic value of glucocorticoid receptor (GR) activation in lung cancer patients was assessed through transcriptomic analyses of public datasets.</div></div><div><h3>Results</h3><div>Pre-treatment with dexamethasone significantly suppressed the apoptosis mediated by multiple chemotherapeutic agents in lung cancer cells. Pulmonary metastatic mouse models showed dexamethasone pre-treatment markedly reduced the anti-tumor efficiency of paclitaxel. Stemness-related properties of lung cancer were significantly improved after dexamethasone treatment, which manifested with enhanced self-renewal capability, improved chemoresistance, and increased tumor initiating potential <em>in vivo</em>. Moreover, we revealed the chemoresistance and stemness properties induced by dexamethasone were depended on GR-mediated nuclear translocation of β-catenin. The N-terminal domain (NTD) and activation function 2 (AF2) region of GR mediated the major contribution in the interaction with β-catenin. Analyses of clinical samples from TCGA-LUAD and GEO datasets demonstrated GR activation was associated with worse survival and less benefits from chemotherapy in lung cancer patients.</div></div><div><h3>Conclusions</h3><div>These results revealed dexamethasone could promote chemoresistance and stemness in lung cancer by inducing nuclear-translocation of GR/β-catenin complex. In the long run, more cautions are needed when glucocorticoids are prescribed to patients during chemotherapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101331"},"PeriodicalIF":21.7,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145598828","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}

{"title":"Endothelial cells sense temozolomide resistance to facilitate monocyte-derived macrophage infiltration in glioblastoma","authors":"Wei Gao ,&nbsp;Jianliang Huang ,&nbsp;Kun Deng ,&nbsp;Xiang Lin ,&nbsp;Xinmiao Long ,&nbsp;Xuetong Li ,&nbsp;Meng Huang ,&nbsp;Xiangyu Wang ,&nbsp;Xiaoling She ,&nbsp;Qing Liu ,&nbsp;Minghua Wu","doi":"10.1016/j.drup.2025.101329","DOIUrl":"10.1016/j.drup.2025.101329","url":null,"abstract":"<div><h3>Aims</h3><div>Glioblastoma (GBM), particularly mesenchymal and recurrent GBM, often develops resistance to temozolomide (TMZ) and is characterized by extensive infiltration of monocyte-derived macrophages (MDM), which contributes to treatment failure. However, the mechanisms through which TMZ-resistant GBM recruits MDM remain poorly understood. This study aims to investigate the molecular drivers of MDM infiltration in the context of TMZ resistance and to identify potential therapeutic targets to disrupt this process.</div></div><div><h3>Methods</h3><div>Patient-derived GBM organoid (GBO) was utilized as a model system. We performed molecular profiling to identify genes upregulated in TMZ-resistant recurrent GBO. Endothelial cells (ECs) cultures and preclinical GBM models were used to examine disruption of tight junctions and monocyte infiltration. Mechanistic studies employed genetic knockdown, pharmacological inhibition, and assays, including Chromatin immunoprecipitation-quantitative PCR, Western blot, and immunostaining, to validate pathway activity and protein interactions.</div></div><div><h3>Results</h3><div>COL6A1 (Collagen type VI alpha 1 chain) was significantly upregulated in TMZ-resistant recurrent GBO and associated with poor survival. COL6A1 is bound to ITGB1 (Integrin beta-1) on ECs, leading to disruption of tight junctions via UBD (Ubiquitin-like modifier D)-mediated degradation of claudin-5. Furthermore, COL6A1 activated the FAK/SRC/Hippo/YAP signaling axis, which promoted lactylation of the transcription factor IKZF1 (IKAROS family zinc finger 1) at lysine 255. Lactylated IKZF1 translocated to the nucleus and recruited the chromatin remodeler Chromodomain-helicase-DNA-binding protein 1 to enhance UBD transcription, thereby promoting endothelial barrier breakdown and monocyte infiltration. Treatment with lenalidomide (LEN), an IKZF1 inhibitor, restored claudin-5 expression, reduced MDM accumulation, and re-sensitized TMZ-resistant tumors to chemotherapy in preclinical models.</div></div><div><h3>Conclusion</h3><div>This study identifies a novel signaling cascade whereby TMZ-resistant GBM secretes COL6A1 to activate an IKZF1-UBD axis in ECs, disrupting blood vessel integrity and facilitating MDM infiltration. Our findings delineate the pivotal mechanism by which tumor cells engage ECs to drive MDM infiltration - a linchpin part of the positive-feedback loop that couples TMZ resistance to MDM influx. Targeting IKZF1 with LEN represents a promising strategy for restoring endothelial barrier function, reducing MDM infiltration, and enhancing chemosensitivity in GBM.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101329"},"PeriodicalIF":21.7,"publicationDate":"2025-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145575463","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}

{"title":"Integration of blaOXA-48 into a Col156 plasmid drove a carbapenem-resistant Escherichia coli ST131 outbreak in New Zealand: Global genomic evidence for the gene’s multilayered dissemination","authors":"Rhys T. White ,&nbsp;Craig N. Thornley ,&nbsp;Max Bloomfield ,&nbsp;Kristin Dyet ,&nbsp;Juliet Elvy ,&nbsp;Hermes Perez ,&nbsp;Allan Hardaker ,&nbsp;Michael Harrington ,&nbsp;Simon Jackson ,&nbsp;Matthew Kelly ,&nbsp;Loushy Mangalasseril ,&nbsp;Annette Nesdale ,&nbsp;Xiaoyun Ren ,&nbsp;Jenny Szeto ,&nbsp;Claire Underwood ,&nbsp;David Winter ,&nbsp;Rosemary Woodhouse ,&nbsp;Zuyu Yang","doi":"10.1016/j.drup.2025.101327","DOIUrl":"10.1016/j.drup.2025.101327","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the genetic diversity in OXA-48-producing <em>Escherichia coli</em> ST131 in a New Zealand community outbreak, and to characterize the mobile genetic elements carrying <em>bla</em>_OXA-48, with emphasis on the gene’s global dissemination.</div></div><div><h3>Methods</h3><div>Forty outbreak isolates underwent short-read sequencing; 36 also underwent long-read sequencing. Bayesian phylogenetics reconstructed the emergence and spread of the outbreak. A pangenome graph of 543 Col156 plasmids and 806 global <em>bla</em>_OXA-48-positive contigs were analyzed to assess structural diversity, mobility, and global distribution.</div></div><div><h3>Results</h3><div>The outbreak clone likely emerged circa 2017, following a single introduction into New Zealand after acquiring <em>bla</em>_OXA-48 on a 7872 bp Col156 plasmid. It shares ancestry (circa 2009) with Southeast Asian <em>E. coli</em> ST131 genomes. Long-read sequencing and pangenome graph analyses identified a single IS<em>1</em>-mediated transposition of <em>bla</em>_OXA-48 into a Col156 plasmid backbone, observed across species and continents. Globally, <em>bla</em>_OXA-48 is present in diverse plasmid contexts and insertion sequence arrangements and is widely distributed among Enterobacterales.</div></div><div><h3>Conclusions</h3><div>This is the first high-resolution genomic reconstruction of a community-associated <em>bla</em>_OXA-48 outbreak, identifying a compact Col156 plasmid as a key vector driving carbapenem resistance. Our findings demonstrate the value of complete genome assemblies and pangenome graph analyses in resolving the structural and evolutionary dynamics of antimicrobial resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101327"},"PeriodicalIF":21.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145559712","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}

{"title":"Ferroptosis and the cGAS–STING pathway into precision nano-immuno-theranostics: A mechanistic paradigm for reversing drug resistance in hepatocellular carcinoma","authors":"Alaa Elmetwalli","doi":"10.1016/j.drup.2025.101326","DOIUrl":"10.1016/j.drup.2025.101326","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) represents a formidable therapeutic challenge, with intrinsic and acquired resistance mechanisms severely limiting treatment efficacy and contributing to dismal patient outcomes. This comprehensive review examines the emerging paradigm of precision nano-immuno-theranostics, specifically focusing on ferroptosis-STING coupled platforms as innovative strategies for overcoming multifaceted HCC resistance. This study systematically analyzes five key nanotechnology approaches: lipid nanoparticles (LNPs) for dual-cargo delivery, GPC3-targeted immunotherapeutic platforms, multimodal theranostic systems, sonodynamic therapy constructs, and spatial transcriptomics-guided precision designs. The strategic integration of ferroptosis induction—an iron-dependent cell death mechanism uniquely suited to the iron-rich hepatic microenvironment—with cGAS-STING pathway activation establishes a bidirectional synergistic loop wherein ferroptotic tumor death generates endogenous STING activation, which reciprocally sensitizes cancer cells to ferroptosis. This dual-targeting approach converts immunologically \"cold\" HCC tumors into inflamed \"hot\" therapeutic targets, achieving 78–91 % tumor growth inhibition and 4.2–4.8-fold increases in CD8 + tumor-infiltrating lymphocytes in preclinical models, substantially exceeding conventional monotherapies (sorafenib: 45–52 %; checkpoint inhibitors: 35–48 %). Mechanistically, ferroptosis-STING coupling simultaneously addresses three critical resistance modalities: chemoresistance through GPX4/NRF2 axis collapse, immunoresistance via tumor microenvironment reprogramming, and metabolic resistance by disrupting HIF-1α/STAT3-mediated adaptation. Despite compelling preclinical evidence, translation to clinical practice faces substantial challenges in manufacturing scalability, regulatory approval pathways for combination nanotechnology products, biomarker-driven patient stratification, and long-term safety assessment. This review critically evaluates current nano-immuno-theranostic platforms, provides quantitative comparative analysis against existing HCC therapies, identifies critical translational gaps, and proposes strategic solutions spanning adaptive regulatory frameworks, continuous manufacturing innovations, and precision medicine integration. The convergence of nanotechnology, immunotherapy, and multi-omic profiling offers unprecedented opportunities for developing next-generation HCC therapeutics capable of dismantling the complex resistance networks that characterize this aggressive malignancy, with first-in-human trials anticipated in 2025–2027 and potential regulatory approval trajectories extending to 2030.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101326"},"PeriodicalIF":21.7,"publicationDate":"2025-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509260","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}

{"title":"Three decades of ESKAPEE antimicrobial resistance: Emerging burdens in working-age individuals and high-income regions","authors":"Xiuling Song,&nbsp;Liang Wang,&nbsp;Bing Gu","doi":"10.1016/j.drup.2025.101325","DOIUrl":"10.1016/j.drup.2025.101325","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101325"},"PeriodicalIF":21.7,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145498786","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}

{"title":"Loss of cyclin C drives resistance to anti-TIGIT therapy by upregulating CD155-mediated immune evasion","authors":"Shiyu Mao ,&nbsp;Yadong Guo ,&nbsp;Chengyuan Dong ,&nbsp;Dongdong Wang ,&nbsp;Xinbo Wang ,&nbsp;Linjun Weng ,&nbsp;Yanrong Yang ,&nbsp;Yaxu Li ,&nbsp;Tingting Niu ,&nbsp;Qi Wu ,&nbsp;Zening Zheng ,&nbsp;Zezhi Shan ,&nbsp;Xiao Tan ,&nbsp;Yaohui Gao ,&nbsp;Jiali Jin ,&nbsp;Ping Wang ,&nbsp;Xin Ge ,&nbsp;Bing Shen ,&nbsp;Xudong Yao ,&nbsp;Lan Fang","doi":"10.1016/j.drup.2025.101318","DOIUrl":"10.1016/j.drup.2025.101318","url":null,"abstract":"<div><h3>Aims</h3><div>CD155 is an immune checkpoint protein expressed in tumor cells that interacts with its ligand T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on natural killer (NK) cells and T cells, mediating inhibitory regulation on immune cells. Blockade of the CD155-TIGIT interaction has demonstrated clinical benefits in patients with advanced cancers. The transcriptional and post-translational mechanisms governing CD155 expression remain largely unknown.</div></div><div><h3>Methods</h3><div>To identify regulators of CD155, we conducted a genome-wide CRISPR-Cas9 screen in cancer cells. Surface CD155 protein levels were analyzed via flow cytometry. The role of candidate regulators was validated through loss- and gain-of-function experiments with flow cytometry, Western blot, quantitative PCR, and chromatin immunoprecipitation (ChIP) assays. Additionally, ubiquitination assay was performed to examine post-translational modifications. Functional studies, including NK and T cell cytotoxicity assays, were conducted to assess the immune modulatory effects of CD155 regulation. Clinical relevance was evaluated by analyzing Cyclin C (CCNC) and CD155 expression in datasets of cancer patients who underwent immune checkpoint blockade therapy.</div></div><div><h3>Results</h3><div>The CRISPR-Cas9 screen identified CCNC as a transcriptional suppressor of CD155. <em>CCNC</em> knockout led to increased surface CD155 expression in cancer cell lines. Mechanistically, CCNC inhibited CD155 transcription by suppressing the activity of the transcription factor FOSL2. Furthermore, CCNC was found to be ubiquitinated and degraded by the E3 ubiquitin ligase FBXO11, suggesting a post-translational regulatory mechanism. Functionally, loss of CCNC promoted CD155 upregulation, thereby enhancing tumor immune evasion from NK and T cell-mediated responses. Clinically, CCNC expression was negatively correlated with CD155 levels in cancer patients, particularly those receiving immune checkpoint blockade therapy.</div></div><div><h3>Conclusion</h3><div>This study identifies a previously unrecognized master regulator CCNC that functions as a suppressor of CD155-mediated cancer immune evasion. The findings of this study suggest that tumors with low CCNC expression may be resistant to monotherapy and highlight a combination immunotherapy (TIGIT/PD-1 co-blockade) as a promising anti-cancer therapeutic strategy to overcome immune evasion in CCNC-deficient tumors.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101318"},"PeriodicalIF":21.7,"publicationDate":"2025-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145485479","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}