Drug Resistance Updates最新文献

{"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}

{"title":"Y10 phosphorylation of LDHA promotes the release of extracellular vesicle-derived circSEPT9 to enhance the chemoresistance of triple negative breast cancer cells via modulation of miR-515–5p/KIAA1429 axis","authors":"Yueping Wang ,&nbsp;Ziyun Zhang ,&nbsp;Juan Gu ,&nbsp;Ming Zhou ,&nbsp;Jiankang Huang ,&nbsp;Daoping Zhou ,&nbsp;Xuedong Wang","doi":"10.1016/j.drup.2025.101324","DOIUrl":"10.1016/j.drup.2025.101324","url":null,"abstract":"<div><h3>Objective</h3><div>Extracellular vesicle (EV)-derived RNAs play crucial roles in cancer biology and therapeutic resistance. This study investigated how EV-derived circSEPT9 mediates doxorubicin (DOX) resistance in triple negative breast cancer (TNBC).</div></div><div><h3>Methods</h3><div>TNBC tissues and samples were analyzed alongside MDA-MB-231 and MDA-MB-231/ADR cells. The molecular interplay among circSEPT9, KIAA1429, and miR-515–5p was explored to elucidate the regulatory axis underlying drug resistance. EVs were purified to assess the clinical diagnostic potential of EV-circSEPT9. Functional assays employing lactate dehydrogenase A (LDHA) knockdown and rescue with Flag-tagged human LDHA WT or Y10F mutant constructs were conducted to examine the significance of LDHA Y10 phosphorylation in EV-circSEPT9 release and DOX resistance.</div></div><div><h3>Results</h3><div>circSEPT9 silencing impaired proliferation, invasion, and colony formation of DOX-resistant TNBC cells while increasing their sensitivity to DOX through suppression of KIAA1429-mediated m6A modification. EVs from resistant cells transferred circSEPT9 to sensitive cells, thereby enhancing their drug resistance and tumor growth capacity. LDHA Y10 phosphorylation was found to be indispensable for EV-circSEPT9 secretion and the subsequent intercellular transfer of DOX resistance.</div></div><div><h3>Conclusion</h3><div>Phosphorylated LDHA (Y10) promotes EV-circSEPT9 secretion, elevating intracellular circSEPT9 levels in recipient TNBC cells. By functioning as a competing endogenous RNA (ceRNA) that sponges miR-515–5p, circSEPT9 upregulates KIAA1429, augments m6A methylation, and drives the development of chemoresistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101324"},"PeriodicalIF":21.7,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145462288","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":"Metabolite-driven reprogramming of bacterial persisters: Mechanisms and therapeutic opportunities for overcoming antibiotic tolerance","authors":"Yixiao Song ,&nbsp;Zifan Ye ,&nbsp;Yipeng Wang","doi":"10.1016/j.drup.2025.101322","DOIUrl":"10.1016/j.drup.2025.101322","url":null,"abstract":"<div><div>Bacterial persisters constitute a heterogeneous subpopulation of dormant or slow-growing cells capable of surviving harsh environmental conditions, including antibiotic exposure. These cells are strongly associated with the failure of clinical antibiotic therapies and the recurrence of chronic bacterial infections. A comprehensive understanding of the physiological features of bacterial persisters is therefore critical for the development of targeted interventions aimed at overcoming the limitations of conventional antibiotic treatments. In this review, we summarize current models of bacterial persister formation, with particular emphasis on the pivotal role of reduced metabolic activity in mediating antibiotic tolerance. We further elucidate the mechanisms through which exogenous metabolites—such as sugars, lipids, and nucleic acid derivatives—induce metabolic reprogramming, thereby reversing multidrug resistance in bacterial persisters. Furthermore, we summarized the major barriers limiting the clinical translation of metabolite-assisted “wake-and-kill” strategies and outlined future prospects for their application. In conclusion, restoring bacterial metabolic activity through targeted metabolite interventions represents a promising avenue to overcome antibiotic tolerance, paving the way for next-generation therapeutic strategies against persistent infections.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101322"},"PeriodicalIF":21.7,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441918","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":"Nanoparticles-mediated mitochondrial relocation of lipid-lowering drugs shape energy metabolism to conquer acquired immune resistance","authors":"Cheng Li ,&nbsp;Wei Xiong ,&nbsp;Jiahao Liu ,&nbsp;Ke Li ,&nbsp;Haoxiang Wang ,&nbsp;Zhengxiang Wang ,&nbsp;Feiyu Liu ,&nbsp;Jianliang Shen ,&nbsp;Zaigang Zhou ,&nbsp;Shenpeng Ying ,&nbsp;Long Wang","doi":"10.1016/j.drup.2025.101323","DOIUrl":"10.1016/j.drup.2025.101323","url":null,"abstract":"<div><div>CD276, is a fatal recently discovered immune checkpoint proteins of B7 family. Due to the not clearly uncovered signal pathways that involved in the expression of CD276 in tumors, few strategies were discovered to regulate CD276. Here, we newly discovered that abnormal tumor mitochondrial activation played a vital important role in raising CD276 expression through targeting AMPK/mTOR signal pathway. Then, it was also revealed that clinical usable lipid-lowering drugs with mitochondria oxidative phosphorylation (OXPHOS) and glycolysis inhibiting capacity, like fenofibric acid (FFA), exhibited desired programmed death ligand-1 (PD-L1) and CD276 co-suppression capacity. To better deliver FFA to tumor mitochondria, IR-FFA was synthesized by linking the mitochondria-targeting heptamethylene cyanine IR-68 with FFA, followed by self-assembly with albumin (Alb) to create IR-FFA@Alb nanoparticles. By doing so, the dosage needed for IR-FFA@Alb to depress CD276 and PD-L1 expression was 100 times lower than free FFA. Then, IR-FFA@Alb monotherapy effectively inhibited tumor growth both <em>in vitro</em> and <em>in vivo</em>. Moreover, the combination therapy of IR-FFA@Alb nanoparticles and radiotherapy (RT) effectively avoid the frequently occurred immune tolerance phenomenon of RT by co-depression CD276 and PD-L1. These results altogether showed the possibility of using lipid-lowering drugs as multi-functional immune checkpoint inhibitors to sensitize tumor therapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101323"},"PeriodicalIF":21.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441447","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":"Disruption of NANOG-driven epithelial-mesenchymal transition (EMT) and self-renewal restores drug sensitivity in colorectal cancer","authors":"Kiarash Saleki ,&nbsp;Sameerah Shaheen ,&nbsp;Miao Xue ,&nbsp;Amirreza Mazloomi ,&nbsp;Sepideh Youssefi ,&nbsp;Hossein Kashfi ,&nbsp;Mehreen Ahmed ,&nbsp;Roya Babaei-Jadidi ,&nbsp;Bradley Spencer-Dene ,&nbsp;Dominique Bonnet ,&nbsp;Chris Denning ,&nbsp;Abdolrahman S. Nateri","doi":"10.1016/j.drup.2025.101321","DOIUrl":"10.1016/j.drup.2025.101321","url":null,"abstract":"<div><h3>Aims</h3><div>To investigate the regulatory role of NANOG in genes associated with stemness, symmetric division, and therapeutic resistance in colorectal cancer stem-like cells (CRC-SCs), with a focus on ERK/GSK-3β/β-catenin signalling and epithelial-mesenchymal transition (EMT), in order to evaluate the translational potential of targeting NANOG-associated signalling pathways.</div></div><div><h3>Methods</h3><div>Stemness, signalling activity, and cell division modes were analysed using 3D colonospheres enriched for CRC-SCs. Drug responses to the MEK inhibitor U0126 and the GSK-3β inhibitor TDZD-8 were assessed in CRC patient-derived organoids (PDOs), alongside molecular assays, immunohistochemistry with H-score quantification in xenograft models, and molecular dynamics simulations.</div></div><div><h3>Results</h3><div>NANOG overexpression enhanced the expression of stemness-associated genes, promoted symmetric cell division, and activated ERK/GSK-3β signalling, contributing to increased sphere formation. Inhibition of MEK and GSK-3β reduced EMT, cell proliferation, and symmetric division in CRC-SCs. NANOG-mediated dysregulation of ERK/GSK-3β altered β-catenin signalling and disrupted E-cadherin-dependent cell-cell adhesion. Molecular simulations and drug assays demonstrated that TDZD-8 and U0126 interfere with NANOG-DNA binding and β-catenin/E-cadherin interactions.</div></div><div><h3>Conclusions</h3><div>NANOG drives CRC-SC maintenance via ERK/GSK-3β/β-catenin signalling and EMT modulation. This study offers significant insights into the translational impact of targeting NANOG and its downstream pathways with small-molecule inhibitors U0126 and TDZD-8 and presents a promising strategy to reduce CRC-SCs stemness, functionality, and tumourigenicity.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101321"},"PeriodicalIF":21.7,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145441940","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 role of synthetic lethality in overcoming cancer therapy resistance: Emerging paradigm and recent advances.","authors":"Qingyi Xiong, Jinmei Jin, Jiayi Lin, Bohan Zhang, Yixin Jiang, Zhe Sun, Lijun Zhang, Ye Wu, Guozhi Zhao, Jiang-Jiang Qin, Xin Luan","doi":"10.1016/j.drup.2025.101290","DOIUrl":"10.1016/j.drup.2025.101290","url":null,"abstract":"<p><p>Cancer therapy resistance remains a major barrier to successful treatment, often leading to reduced clinical efficacy or cancer relapse. Synthetic lethality (SL) has emerged as a promising strategy to exploit genetic vulnerabilities in cancer cells, allowing for more selective and less toxic therapies. By leveraging the genetic or non-genetic adaptations that cancer cells develop under therapeutic pressure, SL-based therapies provide a more precise and less toxic treatment approach. Additionally, SL-driven drug combinations not only delay development of drug resistance but also enhance therapeutic efficacy, representing a transformative shift in cancer management. A comprehensive understanding of SL mechanisms in the context of drug resistance is essential for advancing effective treatment strategies. This review highlights recent advances in SL research, emphasizing the gene screening techniques in overcoming cancer therapy resistance.</p>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"101290"},"PeriodicalIF":21.7,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144812629","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":"Peptide nanonet trapping suppresses bacterial motility and delays antibiotic resistance emergence","authors":"Jian Xu ,&nbsp;Nhan Dai Thien Tram ,&nbsp;Peiyan Yu,&nbsp;Dhanya Mahalakshmi Murali,&nbsp;Wei Meng Chen,&nbsp;Samantha Jinglin Yang ,&nbsp;Pui Lai Rachel Ee","doi":"10.1016/j.drup.2025.101320","DOIUrl":"10.1016/j.drup.2025.101320","url":null,"abstract":"<div><h3>Aims</h3><div>In the presence of antibiotics, motile bacteria can navigate chemical gradients for adaptation and survival. Antimicrobial peptides (AMPs) have been widely explored as adjuvant to improve the activity potency of antibiotics, but mainly through the disruption of bacterial membranes. In this work, we investigated the impact of nanonet trapping using fibrillating peptides, a mechanistically unique sub-group of AMPs, on motility recovery of bacteria and their capacity to develop antibiotic resistance.</div></div><div><h3>Methods</h3><div>The ability of fibrillating AMPs to potentiate activity and delay resistance of antibiotics from diverse classes was evaluated against clinical isolates of Gram-negative pathogens. Using soft agar assay and live-tracking microscopy, shifts in the motility of the bacteria population subjected to different treatments were evaluated. To further elucidate the mechanism of action, the expression of major flagella-encoding genes was quantified and hypomotile bacteria strains were studied.</div></div><div><h3>Results</h3><div>At sub-inhibitory concentrations, fibrillating peptides not only displayed synergistic interactions, but also significantly delayed the emergence of resistance to antibiotics such as rifampicin for at least 18 days. The peptide-antibiotic synergy profiles were lost after prolonged treatment with antibiotic monotherapy but preserved when co-administered with fibrillating peptides throughout the serial passage. The nanonet-forming peptides were shown to serve as a motility filter where the bacteria population gradually shifted towards homogeneous hypomotility associated with inferior survivability.</div></div><div><h3>Conclusions</h3><div>This work showcases the potential of AMPs as low-concentration adjuvants for extending the clinical lifespan of current antibiotics and highlights bacterial motility as an underexplored target for antibiotic development.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101320"},"PeriodicalIF":21.7,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382791","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":"ZBP1 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in ovarian cancer","authors":"Shen-nan Shi ,&nbsp;Qiuyang Xu ,&nbsp;Zhiqi Liao ,&nbsp;Wenjian Gong ,&nbsp;Yilin Cui ,&nbsp;Jiahao Liu ,&nbsp;Xiaofei Jiao ,&nbsp;Yijie Wu ,&nbsp;Mengshi Luo ,&nbsp;Yuewen Zhang ,&nbsp;Linghui Wang ,&nbsp;Yuanjia Wen ,&nbsp;Wen Pan ,&nbsp;Xuejiao Zhao ,&nbsp;Marilyne Labrie ,&nbsp;Zhiyong Ding ,&nbsp;Gordon B. Mills ,&nbsp;Ding Ma ,&nbsp;Guang-Nian Zhao ,&nbsp;Qinglei Gao ,&nbsp;Yong Fang","doi":"10.1016/j.drup.2025.101319","DOIUrl":"10.1016/j.drup.2025.101319","url":null,"abstract":"<div><div>ZBP1, a classic pattern recognition receptor (PRR), has been implicated in regulating programmed cell death and the innate immune response. However, the role of ZBP1 in the nucleus remains largely undefined. Here, we found that nuclear ZBP1 localizes to the site of DNA double-stranded breaks (DSBs) following DNA damage and impairs homologous recombination (HR) repair through its interaction with MRE11. ZBP1 interacts with MRE11 through RHIM A and B domains and inhibits the enzymatic activity of MRE11, ultimately leading to the suppression of HR and DNA damage repair (DDR). These processes are initiated via ATM-mediated ZBP1 phosphorylation at S106. Consistent with these findings, <em>in vitro</em> and <em>in vivo</em> models both exhibit increased sensitivity to PARP inhibitor treatment following ZBP1 overexpression. Furthermore, in our neoadjuvant niraparib monotherapy study (NCT05407841) higher ZBP1 expression correlates with better response to PARP inhibition and prolonged PFS in high-grade serous ovarian cancer (HGSOC). This study describes a novel function of ZBP1 for regulating HR, which confers synthetic lethality to PARP inhibition in ovarian cancer. ZBP1 thus serves as a potential therapy target and biomarker of response to PARP inhibitors and potentially other therapeutic agents such as platin analogs that are synthetically lethal with defective HR.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101319"},"PeriodicalIF":21.7,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145382804","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":"Metabolic basis of fatty acid oxidation and immunotherapy resistance with clinical perspectives","authors":"Junfeng Zhang,&nbsp;Jianyou Gu","doi":"10.1016/j.drup.2025.101317","DOIUrl":"10.1016/j.drup.2025.101317","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101317"},"PeriodicalIF":21.7,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363516","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 novel strategy to overcome the drug-resistant lung cancer: Dual targeting delivery of PROTAC to inhibit cancer-associated fibroblasts and lung cancer cells","authors":"Lingmin Zhang ,&nbsp;Linlong He ,&nbsp;Yinshan Lin ,&nbsp;Juyan Wei ,&nbsp;Shiqi Tang ,&nbsp;Xueping Lei ,&nbsp;Xufeng Lin ,&nbsp;Dazhi Zhou ,&nbsp;Liwu Fu ,&nbsp;Yuehua Li ,&nbsp;Juyun He ,&nbsp;Lu Liang ,&nbsp;Xi-Yong Yu","doi":"10.1016/j.drup.2025.101316","DOIUrl":"10.1016/j.drup.2025.101316","url":null,"abstract":"<div><div>Current pharmacotherapy on the fatal lung cancer is often limited by the development of drug resistance, which significantly contributes to treatment failure. The drug resistance in cancer is associated with tumor microenvironment (TME), particularly with cancer-associated fibroblasts (CAFs). However, the present approaches show little progress in the eliminating lung cancer cells and reversing the TME synergistically. The emergence of nanomedicine offers promising strategies to overcome this challenge. In this study, we developed a proteolysis-targeting chimeras (PROTAC)-based nanodrug, designed to eliminate both lung cancer cells and CAFs, thereby amplifying the therapeutic effects. This nanodrug was constructed by loading dBET6 with US Food and Drug Administration (FDA) approved polymer Poly(lactic-co-glycolic acid) (PLGA), and further camouflaged with the hybrid membranes derived from platelet and lung cancer cells (PLMPD). PLMPD demonstrated excellent dual-targeting capabilities to both lung cancer cells and CAFs, leading to significant apoptosis in both cell types in vitro. We also found that PLMPD could inhibited the growth of Osimertinib-resistant cells. In vivo studies revealed that PLMPD enhanced tumor targeting, effectively inhibited tumor growth, and reversed the tumor-promoting TME in the lung cancer xenograft models. These findings underscore the potential of PLMPD as a promising PROTAC-based nanodrug for lung cancer therapy, offering a new avenue for overcoming drug resistance and improving treatment outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101316"},"PeriodicalIF":21.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363515","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}