Pub Date : 2025-07-18DOI: 10.1016/j.drup.2025.101277
Qing-Qing Chai , Dan Li , Min Zhang , Yong-Wei Gu , Ai-Xue Li , Xin Wu , Xiao-Yan Liu , Ji-Yong Liu
Resistance to cancer therapy is driven by physical barriers, tumor heterogeneity, selective therapeutic pressure, immunosuppressive tumor microenvironment (TME) and others. Bacterial outer membrane vesicles (OMVs) represent a promising nanotherapeutic platform to combat cancer therapy resistance. This review discusses the dual roles of OMVs in tumorigenesis and cancer therapy, highlighting their potential applications to enhance treatment efficacy. OMVs from pathogenic bacteria, such as Fusobacterium nucleatum and Helicobacter pylori, exacerbate chemoresistance by reshaping TME through hypoxia-induced metabolic reprogramming and immune evasion, while OMVs from some bacteria, such as probiotics, counteract immunosuppression by promoting cytotoxic T-cell infiltration and macrophage polarization. As bio-derived and conveniently engineered drug delivery platforms, OMVs maximize the synergetic anticancer effect by pathogen associated molecular patterns and the payloads. These functional payloads include siRNAs, cytotoxicity and molecular agents, and immune checkpoint inhibitors. Bacterial OMVs demonstrate unique advantages through their capacity to penetrate physical barriers, achieve tumor-specific targeting, activate immune responses, to overcome cancer therapy resistance. A successful example is the OMV-based nanoplatform with engineered OMVs co-delivering CD47-siRNA and doxorubicin to overcome drug resistance by inducing immunogenic cell death and dendritic cell activation of glioblastoma. Furthermore, OMV-based cancer vaccines presented with tumor antigens or hybridized with tumor-derived membranes enhance dendritic cell maturation and antigen-specific T-cell responses, reversing treatment resistance. By addressing challenges in mass production and safety concerns, OMVs-based platforms can be developed as powerful tools for more effective and personalized cancer treatments.
{"title":"Engineering nanoplatforms of bacterial outer membrane vesicles to overcome cancer therapy resistance","authors":"Qing-Qing Chai , Dan Li , Min Zhang , Yong-Wei Gu , Ai-Xue Li , Xin Wu , Xiao-Yan Liu , Ji-Yong Liu","doi":"10.1016/j.drup.2025.101277","DOIUrl":"10.1016/j.drup.2025.101277","url":null,"abstract":"<div><div>Resistance to cancer therapy is driven by physical barriers, tumor heterogeneity, selective therapeutic pressure, immunosuppressive tumor microenvironment (TME) and others. Bacterial outer membrane vesicles (OMVs) represent a promising nanotherapeutic platform to combat cancer therapy resistance. This review discusses the dual roles of OMVs in tumorigenesis and cancer therapy, highlighting their potential applications to enhance treatment efficacy. OMVs from pathogenic bacteria, such as <em>Fusobacterium nucleatum</em> and <em>Helicobacter pylori</em>, exacerbate chemoresistance by reshaping TME through hypoxia-induced metabolic reprogramming and immune evasion, while OMVs from some bacteria, such as probiotics, counteract immunosuppression by promoting cytotoxic T-cell infiltration and macrophage polarization. As bio-derived and conveniently engineered drug delivery platforms, OMVs maximize the synergetic anticancer effect by pathogen associated molecular patterns and the payloads. These functional payloads include siRNAs, cytotoxicity and molecular agents, and immune checkpoint inhibitors. Bacterial OMVs demonstrate unique advantages through their capacity to penetrate physical barriers, achieve tumor-specific targeting, activate immune responses, to overcome cancer therapy resistance. A successful example is the OMV-based nanoplatform with engineered OMVs co-delivering CD47-siRNA and doxorubicin to overcome drug resistance by inducing immunogenic cell death and dendritic cell activation of glioblastoma. Furthermore, OMV-based cancer vaccines presented with tumor antigens or hybridized with tumor-derived membranes enhance dendritic cell maturation and antigen-specific T-cell responses, reversing treatment resistance. By addressing challenges in mass production and safety concerns, OMVs-based platforms can be developed as powerful tools for more effective and personalized cancer treatments.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101277"},"PeriodicalIF":15.8,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665099","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}
Pub Date : 2025-07-17DOI: 10.1016/j.drup.2025.101276
Mingyang Jiang , Jinlong Wang , Yize Li , Ke Zhang , Tao Wang , Zhandong Bo , Shenyi Lu , Raquel Alarcón Rodríguez , Ruqiong Wei , Mingtao Zhu , Christophe Nicot , Gautam Sethi
Cancer continues to be a primary cause of death, resulting in substantial mortality and illness globally. It remains a significant global health issue, greatly affecting morbidity and mortality across the world. Therapeutic resistance poses a major challenge to cancer treatments, acting as a significant barrier to the effectiveness of both standard and targeted therapies. This resistance develops through various mechanisms that allow tumor cells to adapt to and escape the damaging effects of chemotherapy, radiation, and targeted therapies. Ultimately, this leads to disease recurrence and progression. This review examines the dual roles of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in promoting chemoresistance and metastasis. EMT is a dynamic and reversible biological process in which epithelial cells acquire mesenchymal characteristics, increasing their invasiveness and resistance to programmed cell death. CSCs are a subset of cancer cells with the ability to self-renew and play a crucial role in tumor relapse and resistance to treatment. EMT and CSCs are closely interconnected, collaboratively enhancing cancer cell plasticity, metastatic ability, and treatment resistance. The initiation of EMT in cancer cells can generate a CSC-like population, which promotes tumor recurrence and spread. This interaction highlights the importance of targeting both EMT and CSC pathways to develop more effective treatment strategies that address treatment resistance and prevent metastasis. Promising approaches include using natural substances, small molecules, and nanotechnology to block critical signaling pathways and interfere with resistance mechanisms. A more thorough understanding of the molecular factors underlying EMT and CSC plasticity is crucial for crafting personalized treatments that target tumor heterogeneity and improve clinical outcomes.
{"title":"EMT and cancer stem cells: Drivers of therapy resistance and promising therapeutic targets","authors":"Mingyang Jiang , Jinlong Wang , Yize Li , Ke Zhang , Tao Wang , Zhandong Bo , Shenyi Lu , Raquel Alarcón Rodríguez , Ruqiong Wei , Mingtao Zhu , Christophe Nicot , Gautam Sethi","doi":"10.1016/j.drup.2025.101276","DOIUrl":"10.1016/j.drup.2025.101276","url":null,"abstract":"<div><div>Cancer continues to be a primary cause of death, resulting in substantial mortality and illness globally. It remains a significant global health issue, greatly affecting morbidity and mortality across the world. Therapeutic resistance poses a major challenge to cancer treatments, acting as a significant barrier to the effectiveness of both standard and targeted therapies. This resistance develops through various mechanisms that allow tumor cells to adapt to and escape the damaging effects of chemotherapy, radiation, and targeted therapies. Ultimately, this leads to disease recurrence and progression. This review examines the dual roles of epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) in promoting chemoresistance and metastasis. EMT is a dynamic and reversible biological process in which epithelial cells acquire mesenchymal characteristics, increasing their invasiveness and resistance to programmed cell death. CSCs are a subset of cancer cells with the ability to self-renew and play a crucial role in tumor relapse and resistance to treatment. EMT and CSCs are closely interconnected, collaboratively enhancing cancer cell plasticity, metastatic ability, and treatment resistance. The initiation of EMT in cancer cells can generate a CSC-like population, which promotes tumor recurrence and spread. This interaction highlights the importance of targeting both EMT and CSC pathways to develop more effective treatment strategies that address treatment resistance and prevent metastasis. Promising approaches include using natural substances, small molecules, and nanotechnology to block critical signaling pathways and interfere with resistance mechanisms. A more thorough understanding of the molecular factors underlying EMT and CSC plasticity is crucial for crafting personalized treatments that target tumor heterogeneity and improve clinical outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"83 ","pages":"Article 101276"},"PeriodicalIF":21.7,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144725039","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}
Pub Date : 2025-07-14DOI: 10.1016/j.drup.2025.101275
Jiajin Xu , Shuo Fang , Xiaotong Dong , Chengdong Liang , Ruoyu Yang , Yang Zhao , Hailong Gu , Min Fu , Jiahui Zhang , Xiaoxin Zhang , Xu Zhang , Runbi Ji
Chemotherapy resistance is a major cause of poor prognosis in gastric cancer patients and tumor microenvironment plays a critical role in conferring chemotherapy resistance. As a dominant source of tumor stromal cells, mesenchymal stem cells (MSCs) exert pro-oncogenic activities when reprogrammed to a cancer-associated fibroblast (CAF) phenotype. The precise mechanisms for MSC reprogramming and their subsequent role in chemotherapy resistance have not been fully understood. Herein, we reported that HIF1A-AS3, a lncRNA that was highly expressed in tumor-promoting MSCs, was upregulated in tumor tissues and serum of gastric cancer patients and associated with poor prognosis. The upregulation of HIF1A-AS3 reprogramed MSCs to acquire the CAF phenotype, which consequently enhanced the resistance of gastric cancer cells to oxaliplatin. Mechanistically, hypoxia related transcription factor HIF-1α induced high expression of HIF1A-AS3 in MSCs. Then, HIF1A-AS3 competitively sponged miR-142–3p and miR-24–3p, leading to the upregulation of PROX1 (prospero-related homeobox protein 1) gene expression. This further promoted the nuclear translocation of β-catenin and the activation of β-catenin signaling pathway in MSCs, which critically regulated their transition to CAFs. Finally, targeted inhibition of HIF1A-AS3 in hypoxia-MSCs through exosome-mediated siRNA delivery significantly suppressed gastric cancer growth and improved chemosensitivity in mouse tumor models. Conclusively, hypoxia-induced HIF1A-AS3 upregulation reprograms MSCs to CAFs through the miR-142–3p/miR-24–3p/PROX1/β-catenin axis, thereby promoting chemotherapy resistance in gastric cancer, which uncovers a new molecular mechanism for MSCs transition to CAFs in gastric cancer and provides a new target for the diagnosis and targeted therapy of gastric cancer.
化疗耐药是胃癌患者预后不良的主要原因，肿瘤微环境在化疗耐药的形成中起着至关重要的作用。作为肿瘤基质细胞的主要来源，间充质干细胞（MSCs）在重编程为癌症相关成纤维细胞（CAF）表型时发挥促癌活性。MSC重编程的确切机制及其在化疗耐药中的后续作用尚未完全了解。本文中，我们报道了在促肿瘤MSCs中高表达的lncRNA HIF1A-AS3在胃癌患者的肿瘤组织和血清中表达上调，并与不良预后相关。HIF1A-AS3的上调使MSCs重编程获得CAF表型，从而增强胃癌细胞对奥沙利铂的抗性。机制上，缺氧相关转录因子HIF-1α诱导MSCs中高表达HIF1A-AS3。然后，HIF1A-AS3竞争性地海绵化miR-142-3p和miR-24-3p，导致PROX1 （prospero-related homobox protein 1）基因表达上调。这进一步促进了β-catenin的核易位和β-catenin信号通路的激活，这对MSCs向CAFs的转变起着关键的调节作用。最后，在小鼠肿瘤模型中，通过外泌体介导的siRNA递送靶向抑制HIF1A-AS3在缺氧间充质干细胞中显著抑制胃癌生长并改善化疗敏感性。总之，缺氧诱导的HIF1A-AS3上调通过miR-142-3p/miR-24-3p/PROX1/β-catenin轴将MSCs重编程为CAFs，从而促进胃癌的化疗耐药，揭示了胃癌中MSCs向CAFs转变的新的分子机制，为胃癌的诊断和靶向治疗提供了新的靶点。
{"title":"Hypoxia-induced upregulation of HIF1A-AS3 promotes MSC transition to cancer-associated fibroblasts and confers drug resistance in gastric cancer","authors":"Jiajin Xu , Shuo Fang , Xiaotong Dong , Chengdong Liang , Ruoyu Yang , Yang Zhao , Hailong Gu , Min Fu , Jiahui Zhang , Xiaoxin Zhang , Xu Zhang , Runbi Ji","doi":"10.1016/j.drup.2025.101275","DOIUrl":"10.1016/j.drup.2025.101275","url":null,"abstract":"<div><div>Chemotherapy resistance is a major cause of poor prognosis in gastric cancer patients and tumor microenvironment plays a critical role in conferring chemotherapy resistance. As a dominant source of tumor stromal cells, mesenchymal stem cells (MSCs) exert pro-oncogenic activities when reprogrammed to a cancer-associated fibroblast (CAF) phenotype. The precise mechanisms for MSC reprogramming and their subsequent role in chemotherapy resistance have not been fully understood. Herein, we reported that HIF1A-AS3, a lncRNA that was highly expressed in tumor-promoting MSCs, was upregulated in tumor tissues and serum of gastric cancer patients and associated with poor prognosis. The upregulation of HIF1A-AS3 reprogramed MSCs to acquire the CAF phenotype, which consequently enhanced the resistance of gastric cancer cells to oxaliplatin. Mechanistically, hypoxia related transcription factor HIF-1α induced high expression of HIF1A-AS3 in MSCs. Then, HIF1A-AS3 competitively sponged miR-142–3p and miR-24–3p, leading to the upregulation of PROX1 (prospero-related homeobox protein 1) gene expression. This further promoted the nuclear translocation of β-catenin and the activation of β-catenin signaling pathway in MSCs, which critically regulated their transition to CAFs. Finally, targeted inhibition of HIF1A-AS3 in hypoxia-MSCs through exosome-mediated siRNA delivery significantly suppressed gastric cancer growth and improved chemosensitivity in mouse tumor models. Conclusively, hypoxia-induced HIF1A-AS3 upregulation reprograms MSCs to CAFs through the miR-142–3p/miR-24–3p/PROX1/β-catenin axis, thereby promoting chemotherapy resistance in gastric cancer, which uncovers a new molecular mechanism for MSCs transition to CAFs in gastric cancer and provides a new target for the diagnosis and targeted therapy of gastric cancer.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101275"},"PeriodicalIF":15.8,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144665096","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}
Pub Date : 2025-07-12DOI: 10.1016/j.drup.2025.101274
Tianfeng Yang , Suyu Zhang , Kun Nie , Cheng Cheng , Xiuhong Peng , Jian Huo , Yanmin Zhang
Regorafenib (RGF) is a critical second-line therapy for advanced hepatocellular carcinoma (HCC) following disease progression on sorafenib; however, the rapid onset of RGF resistance poses a significant barrier to enhancing patient outcomes. In this study, CRISPR/Cas9 screening in RGF-treated HCC cells identified Zinc Finger Protein 207 (ZNF207) as a primary driver of resistance. Further analysis revealed that ZNF207 promotes resistance by inducing antioxidant responses that inhibit ferroptosis, a form of iron-dependent cell death. Mechanistically, ZNF207 facilitates the lactylation of peroxiredoxin 1 (PRDX1) at lysine 67, enhancing nuclear translocation and activation of nuclear factor erythroid 2–related factor 2 (NRF2), a master regulator of antioxidant pathways. This ZNF207-PRDX1-NRF2 pathway creates a ferroptosis-resistant, pro-survival environment under RGF treatment, enabling HCC cells to evade cell death. Functional assays demonstrated that ZNF207 knockdown significantly enhances RGF sensitivity by restoring ferroptosis, with additional findings showing that disrupting PRDX1 lactylation or NRF2 activity similarly reverses resistance. Together, these findings establish a critical link between protein lactylation and RGF resistance, positioning the ZNF207-PRDX1-NRF2 axis as a promising therapeutic target to enhance treatment efficacy in HCC. The implications of this research extend beyond HCC, indicating that targeting ferroptosis-suppressive pathways may offer a broader approach to overcoming resistance in various cancers.
{"title":"ZNF207-driven PRDX1 lactylation and NRF2 activation in regorafenib resistance and ferroptosis evasion","authors":"Tianfeng Yang , Suyu Zhang , Kun Nie , Cheng Cheng , Xiuhong Peng , Jian Huo , Yanmin Zhang","doi":"10.1016/j.drup.2025.101274","DOIUrl":"10.1016/j.drup.2025.101274","url":null,"abstract":"<div><div>Regorafenib (RGF) is a critical second-line therapy for advanced hepatocellular carcinoma (HCC) following disease progression on sorafenib; however, the rapid onset of RGF resistance poses a significant barrier to enhancing patient outcomes. In this study, CRISPR/Cas9 screening in RGF-treated HCC cells identified Zinc Finger Protein 207 (ZNF207) as a primary driver of resistance. Further analysis revealed that ZNF207 promotes resistance by inducing antioxidant responses that inhibit ferroptosis, a form of iron-dependent cell death. Mechanistically, ZNF207 facilitates the lactylation of peroxiredoxin 1 (PRDX1) at lysine 67, enhancing nuclear translocation and activation of nuclear factor erythroid 2–related factor 2 (NRF2), a master regulator of antioxidant pathways. This ZNF207-PRDX1-NRF2 pathway creates a ferroptosis-resistant, pro-survival environment under RGF treatment, enabling HCC cells to evade cell death. Functional assays demonstrated that ZNF207 knockdown significantly enhances RGF sensitivity by restoring ferroptosis, with additional findings showing that disrupting PRDX1 lactylation or NRF2 activity similarly reverses resistance. Together, these findings establish a critical link between protein lactylation and RGF resistance, positioning the ZNF207-PRDX1-NRF2 axis as a promising therapeutic target to enhance treatment efficacy in HCC. The implications of this research extend beyond HCC, indicating that targeting ferroptosis-suppressive pathways may offer a broader approach to overcoming resistance in various cancers.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101274"},"PeriodicalIF":15.8,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144613303","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}
Pub Date : 2025-07-01DOI: 10.1016/j.drup.2025.101273
Xinhao Zhang , Yuhang Wang , Wenming Cui , Danyang Li , Junmin Song , Zhen Li , Ying Liu , Shuaixi Yang
Drug resistance remains a formidable barrier in modern oncology, undermining the efficacy of the current therapeutic regimens. As pivotal stromal constituents within tumor ecosystems, cancer-associated fibroblasts (CAFs) have emerged as critical mediators of treatment resistance through multifaceted mechanisms. In this review, we summarize the historical progression of research on CAFs and drug resistance, and highlight the recent discoveries related to CAF biomarkers and their functions associated with drug resistance. Furthermore, we discuss the relationship between CAF heterogeneity, secretion, autophagy, and senescence and their contributions to the evolution of drug resistance. Additionally, we provide a detailed explanation of how CAFs contribute to the development of drug resistance in primary tumors, including mechanisms such as immune suppression and evasion, promotion of tumor stemness, angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. We also explored the role of CAFs in metastatic tumors and their association with drug resistance at various metastatic sites, including lymph nodes, brain, lungs, peritoneum, bone, and liver. Finally, we summarize the advancements in clinical trials targeting CAFs, the emerging research on potential therapeutic targets, and anticipating future trends in this area.
{"title":"The multifaceted contributions of cancer-associated fibroblasts to drug resistance in primary and metastatic tumors","authors":"Xinhao Zhang , Yuhang Wang , Wenming Cui , Danyang Li , Junmin Song , Zhen Li , Ying Liu , Shuaixi Yang","doi":"10.1016/j.drup.2025.101273","DOIUrl":"10.1016/j.drup.2025.101273","url":null,"abstract":"<div><div>Drug resistance remains a formidable barrier in modern oncology, undermining the efficacy of the current therapeutic regimens. As pivotal stromal constituents within tumor ecosystems, cancer-associated fibroblasts (CAFs) have emerged as critical mediators of treatment resistance through multifaceted mechanisms. In this review, we summarize the historical progression of research on CAFs and drug resistance, and highlight the recent discoveries related to CAF biomarkers and their functions associated with drug resistance. Furthermore, we discuss the relationship between CAF heterogeneity, secretion, autophagy, and senescence and their contributions to the evolution of drug resistance. Additionally, we provide a detailed explanation of how CAFs contribute to the development of drug resistance in primary tumors, including mechanisms such as immune suppression and evasion, promotion of tumor stemness, angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. We also explored the role of CAFs in metastatic tumors and their association with drug resistance at various metastatic sites, including lymph nodes, brain, lungs, peritoneum, bone, and liver. Finally, we summarize the advancements in clinical trials targeting CAFs, the emerging research on potential therapeutic targets, and anticipating future trends in this area.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101273"},"PeriodicalIF":15.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144562800","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}
Pub Date : 2025-06-30DOI: 10.1016/j.drup.2025.101272
Wen Ding , Jianshan Mo , Yingxue Su , Qiyi Zhang , Danyuan Sun , Xiangchao Yao , Guopin Liu , Jiangling Ye , Yanle Wu , Menghan Xue , Peibin Yue , Jinjian Lu , Jian Zhang , Yanyu Shi , Wenhao Hu , Kai Zhu , Yandong Wang , Xiaolei Zhang
Immunosuppression within the tumor microenvironment (TME) is frequently associated with chemoresistance. However, the mechanisms by which chemoresistance promotes immune evasion and impairs subsequent immunotherapy remain poorly understood, underscoring the urgent need for novel therapeutic strategies to counteract these effects. In this study, we observed that tumors exhibit cross-resistance to immunotherapy following chemoresistance in a non-small cell lung cancer (NSCLC) mouse model. The aberrant accumulation of tumor-associated macrophages (TAMs) and extracellular adenosine (Ado) were identified as mediators of immunosuppression, fostering cross-resistance to immunotherapy in the context of chemoresistance. Mechanistically, selective activation of the Ado/A2AR signaling pathway induced metabolic reprogramming of TAMs, thereby creating an immunosuppressive niche in cross-resistant NSCLC. Based on these findings, we designed a novel selective A2AR inhibitor DL082 and explored its therapeutic potential for treating cross-resistant NSCLC. The combination of DL082 with an anti-PD-L1 antibody significantly enhanced immune activation and inhibited tumor progression in cross-resistant NSCLC. These findings elucidate the specific mechanisms underlying cross-resistance between chemotherapy and immunotherapy in NSCLC and propose targeting the Ado-TAM axis as a potential strategy for overcoming resistance in NSCLC therapy.
{"title":"Metabolic reprogramming of tumor-associated macrophages via adenosine-A2AR signaling drives cross-resistance in non-small cell lung cancer","authors":"Wen Ding , Jianshan Mo , Yingxue Su , Qiyi Zhang , Danyuan Sun , Xiangchao Yao , Guopin Liu , Jiangling Ye , Yanle Wu , Menghan Xue , Peibin Yue , Jinjian Lu , Jian Zhang , Yanyu Shi , Wenhao Hu , Kai Zhu , Yandong Wang , Xiaolei Zhang","doi":"10.1016/j.drup.2025.101272","DOIUrl":"10.1016/j.drup.2025.101272","url":null,"abstract":"<div><div>Immunosuppression within the tumor microenvironment (TME) is frequently associated with chemoresistance. However, the mechanisms by which chemoresistance promotes immune evasion and impairs subsequent immunotherapy remain poorly understood, underscoring the urgent need for novel therapeutic strategies to counteract these effects. In this study, we observed that tumors exhibit cross-resistance to immunotherapy following chemoresistance in a non-small cell lung cancer (NSCLC) mouse model. The aberrant accumulation of tumor-associated macrophages (TAMs) and extracellular adenosine (Ado) were identified as mediators of immunosuppression, fostering cross-resistance to immunotherapy in the context of chemoresistance. Mechanistically, selective activation of the Ado/A<sub>2A</sub>R signaling pathway induced metabolic reprogramming of TAMs, thereby creating an immunosuppressive niche in cross-resistant NSCLC. Based on these findings, we designed a novel selective A<sub>2A</sub>R inhibitor DL082 and explored its therapeutic potential for treating cross-resistant NSCLC. The combination of DL082 with an anti-PD-L1 antibody significantly enhanced immune activation and inhibited tumor progression in cross-resistant NSCLC. These findings elucidate the specific mechanisms underlying cross-resistance between chemotherapy and immunotherapy in NSCLC and propose targeting the Ado-TAM axis as a potential strategy for overcoming resistance in NSCLC therapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101272"},"PeriodicalIF":15.8,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563199","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}
Pub Date : 2025-06-13DOI: 10.1016/j.drup.2025.101268
Bowen Ding , Xiaomeng Liu , Zhe Li , Xinru Xie , Jiaqi Li , Jiaqian Wang , Shouyi Li , Pengyu Wang , Yongjie Xie , Xiaoqing Ma , Hongwei Wang , Chengzhi Xie , Xin Qiao , Yumin Wang , Jingyuan Xu , Yukuan Feng , Jihui Hao
{"title":"Corrigendum to “A novel platinum(IV) prodrug, gramine-Pt(IV) enhances chemoimmunotherapy by activating cGAS-STING and modulating TGF-β-MHC-I axis” [Drug Resist. Updates 81 (2025) 101252]","authors":"Bowen Ding , Xiaomeng Liu , Zhe Li , Xinru Xie , Jiaqi Li , Jiaqian Wang , Shouyi Li , Pengyu Wang , Yongjie Xie , Xiaoqing Ma , Hongwei Wang , Chengzhi Xie , Xin Qiao , Yumin Wang , Jingyuan Xu , Yukuan Feng , Jihui Hao","doi":"10.1016/j.drup.2025.101268","DOIUrl":"10.1016/j.drup.2025.101268","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101268"},"PeriodicalIF":15.8,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289795","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}
Pub Date : 2025-06-09DOI: 10.1016/j.drup.2025.101266
Zhenfang Du , Hongfei Kan , Jinghan Sun , Yue Liu , Jiahui Gu , Shugela Akemujiang , Yudi Zou , Lufan Jiang , Qinzhuo Wang , Chen Li , Lei Luo , Yunkai Zhang , Hong Fan , Pengfei Luo , Bo Wang
Tyrosine kinase inhibitors (TKIs) have revolutionized the management of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Despite the initially favorable outcomes, these patients inevitably acquire resistance to EGFR-TKIs. The molecular mechanism of the acquired resistance is highly complex and heterogeneous, and can be generalized as three categories, including EGFR pathway reactivation (re-engagement of EGFR downstream), EGFR pathway bypass (adoption of a parallel pathway to re-engage the downstream transcriptional oncogenic output of the original EGFR), and EGFR pathway indifference (acquirement of a cellular state alternate to the original EGFR-driven output). This review summarizes the recent progress on the identification and understanding of the acquired resistance mechanisms to EGFR-TKIs in patients with NSCLC. The potential strategies to delay or overcome the acquired resistance are also discussed.
{"title":"Molecular mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer","authors":"Zhenfang Du , Hongfei Kan , Jinghan Sun , Yue Liu , Jiahui Gu , Shugela Akemujiang , Yudi Zou , Lufan Jiang , Qinzhuo Wang , Chen Li , Lei Luo , Yunkai Zhang , Hong Fan , Pengfei Luo , Bo Wang","doi":"10.1016/j.drup.2025.101266","DOIUrl":"10.1016/j.drup.2025.101266","url":null,"abstract":"<div><div>Tyrosine kinase inhibitors (TKIs) have revolutionized the management of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Despite the initially favorable outcomes, these patients inevitably acquire resistance to EGFR-TKIs. The molecular mechanism of the acquired resistance is highly complex and heterogeneous, and can be generalized as three categories, including EGFR pathway reactivation (re-engagement of EGFR downstream), EGFR pathway bypass (adoption of a parallel pathway to re-engage the downstream transcriptional oncogenic output of the original EGFR), and EGFR pathway indifference (acquirement of a cellular state alternate to the original EGFR-driven output). This review summarizes the recent progress on the identification and understanding of the acquired resistance mechanisms to EGFR-TKIs in patients with NSCLC. The potential strategies to delay or overcome the acquired resistance are also discussed.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"82 ","pages":"Article 101266"},"PeriodicalIF":15.8,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144261985","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}
Pub Date : 2025-06-07DOI: 10.1016/j.drup.2025.101271
Mingbo Cao , Yuxuan Li , Xiaorui Su , Yongchang Tang , Yupeng Ren , Jing Luo , Feng Yuan , Gaoyuan Yang , Zhiwei He , Zheng Shi , Ziyi Hu , Guirong Liang , Qi Zhang , Meihai Deng , Zhicheng Yao , Nan Lin
Lenvatinib resistance (LR) profoundly exacerbates the prognosis of patients afflicted with advanced hepatocellular carcinoma (HCC). As pivotal mediators of intercellular communication, exosomes have been implicated in the development of LR. Nonetheless, the precise contributions of exosome-derived long non-coding RNAs (lncRNAs) to this phenomenon remain inadequately elucidated. Our prior investigations identified that lnc-FAM72D-3 is markedly up-regulated in the serum exosomes of HCC patients, yet its specific functions and underlying mechanisms remain only partially defined. In this study, we established lenvatinib-resistant HCC cell lines and organoids and demonstrated, through rigorous in vitro and in vivo experiments, that exosome-derived lnc-FAM72D-3 facilitates HCC progression and contributes to the phenomenon of LR. Mechanistically, lnc-FAM72D-3 augments the affinity of the E3 ubiquitin ligase HECTD3 for MBNL1, inciting lysine 48-linked ubiquitination and subsequent degradation of MBNL1. This degradation diminishes the interaction between MBNL1 and focal adhesion kinase (FAK), precipitating the de-nucleation of FAK and its activation by phosphorylation. The activated FAK subsequently reorganizes the cytoskeleton, markedly enhancing the proliferation, invasion, and stemness of HCC cells, thereby fostering LR. In summary, this investigation offers novel mechanistic insights into the regulatory role of exosomal lncRNAs in LR and posits a potential therapeutic strategy aimed at mitigating LR in patients with HCC.
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