Pub Date : 2026-03-01Epub Date: 2026-01-05DOI: 10.1016/j.drup.2026.101352
Lijun Fang , Rongfeng Fu , Huan Dong , Wenhui Zhang , Yuchen Gao , Yanmei Xu , Wenjing Gu , Zixuan Liu , Huiyuan Li , Wentian Wang , Xiaolei Pei , Ying Chi , Yuan Zhou , Jun Wei , Ying Wang , Lei Zhang
Aims
To define JAK2v617f-induced immune alterations, focusing on STAT3-mediated dendritic cell dysfunction, and evaluate whether IFNα2b restores anti-tumor immunity in JAK2v617f-positive myeloproliferative neoplasms.
Methods
Integrated flow cytometry and single-cell RNA sequencing profiled immune landscapes and signaling pathways, while functional assays assessed dendritic cell differentiation, T cell activation, and IFNα2b-mediated immune restoration.
Results
JAK2v617f was associated with increased STAT3 activation in myeloid cells, accompanied by elevated expression of immunosuppressive mediators such as FGL2, impaired monocyte-to-DC differentiation, reduced cDC1/cDC2 subsets, and diminished T cell activation, consistent with an immunosuppressive immune landscape. IFNα2b treatment was associated with attenuation of STAT3/FGL2 signaling and partial restoration of DC-mediated T cell priming, with more pronounced immunomodulatory effects observed in JAK2v617f-positive myeloproliferative neoplasms compared with other subtypes.
Conclusions
Our findings indicate that JAK2v617f is associated with STAT3-dependent dendritic cell dysfunction that contributes to an immunosuppressive milieu. IFNα2b modulates this pathway and partially restores DC–T cell interactions, highlighting its potential as an immunomodulatory strategy in JAK2v617f-positive myeloproliferative neoplasms.
{"title":"IFNα2b modulates anti-tumor immune responses involving STAT3-associated dendritic cell dysfunction in JAK2v617f-positive myeloproliferative neoplasms","authors":"Lijun Fang , Rongfeng Fu , Huan Dong , Wenhui Zhang , Yuchen Gao , Yanmei Xu , Wenjing Gu , Zixuan Liu , Huiyuan Li , Wentian Wang , Xiaolei Pei , Ying Chi , Yuan Zhou , Jun Wei , Ying Wang , Lei Zhang","doi":"10.1016/j.drup.2026.101352","DOIUrl":"10.1016/j.drup.2026.101352","url":null,"abstract":"<div><h3>Aims</h3><div>To define <em>JAK2v617f</em>-induced immune alterations, focusing on STAT3-mediated dendritic cell dysfunction, and evaluate whether IFNα2b restores anti-tumor immunity in <em>JAK2v617f</em>-positive myeloproliferative neoplasms.</div></div><div><h3>Methods</h3><div>Integrated flow cytometry and single-cell RNA sequencing profiled immune landscapes and signaling pathways, while functional assays assessed dendritic cell differentiation, T cell activation, and IFNα2b-mediated immune restoration.</div></div><div><h3>Results</h3><div><em>JAK2v617f</em> was associated with increased STAT3 activation in myeloid cells, accompanied by elevated expression of immunosuppressive mediators such as FGL2, impaired monocyte-to-DC differentiation, reduced cDC1/cDC2 subsets, and diminished T cell activation, consistent with an immunosuppressive immune landscape. IFNα2b treatment was associated with attenuation of STAT3/FGL2 signaling and partial restoration of DC-mediated T cell priming, with more pronounced immunomodulatory effects observed in <em>JAK2v617f</em>-positive myeloproliferative neoplasms compared with other subtypes.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that <em>JAK2v617f</em> is associated with STAT3-dependent dendritic cell dysfunction that contributes to an immunosuppressive milieu. IFNα2b modulates this pathway and partially restores DC–T cell interactions, highlighting its potential as an immunomodulatory strategy in <em>JAK2v617f</em>-positive myeloproliferative neoplasms.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101352"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902552","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 : 2026-03-01Epub Date: 2026-01-06DOI: 10.1016/j.drup.2026.101353
Baris Cerci , Ozge Saatci , Mark Basik , Ozgur Sahin
Antibody-drug conjugate (ADC) is a drug modality where a payload is conjugated to an antibody for its targeted delivery to the cancer cells. In breast cancer, the treatment landscape has changed remarkably in the past decade by the introduction of several effective ADCs in the clinic. However, intrinsic (de novo) or acquired resistance to these treatments is a major obstacle. In this review, we summarize the role of target antigen alterations, cell-intrinsic mechanisms that overcome payload cytotoxicity, and the pro-tumorigenic tumor microenvironment (TME) as the major drivers of resistance to ADCs. Furthermore, we discuss how different mechanisms of ADC resistance are integrated and highlight the most clinically relevant ones. We then provide the current and emerging strategies, such as biomarker-guided drug combinations and novel ADC designs to overcome resistance to ADCs. Finally, we provide future perspectives on the use of preclinical models that better reflect both intratumor heterogeneity and TME, integration of exploratory biomarker analysis through multi-omics of patient biopsies in prospective clinical trials, and development of new ADCs, e.g., bispecific ADCs and identification of novel antigens and/or payloads, to overcome ADC resistance.
{"title":"Mechanisms of resistance to antibody-drug conjugates in breast cancer","authors":"Baris Cerci , Ozge Saatci , Mark Basik , Ozgur Sahin","doi":"10.1016/j.drup.2026.101353","DOIUrl":"10.1016/j.drup.2026.101353","url":null,"abstract":"<div><div>Antibody-drug conjugate (ADC) is a drug modality where a payload is conjugated to an antibody for its targeted delivery to the cancer cells. In breast cancer, the treatment landscape has changed remarkably in the past decade by the introduction of several effective ADCs in the clinic. However, intrinsic (de novo) or acquired resistance to these treatments is a major obstacle. In this review, we summarize the role of target antigen alterations, cell-intrinsic mechanisms that overcome payload cytotoxicity, and the pro-tumorigenic tumor microenvironment (TME) as the major drivers of resistance to ADCs. Furthermore, we discuss how different mechanisms of ADC resistance are integrated and highlight the most clinically relevant ones. We then provide the current and emerging strategies, such as biomarker-guided drug combinations and novel ADC designs to overcome resistance to ADCs. Finally, we provide future perspectives on the use of preclinical models that better reflect both intratumor heterogeneity and TME, integration of exploratory biomarker analysis through multi-omics of patient biopsies in prospective clinical trials, and development of new ADCs, e.g., bispecific ADCs and identification of novel antigens and/or payloads, to overcome ADC resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101353"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925903","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 : 2026-03-01Epub Date: 2025-11-29DOI: 10.1016/j.drup.2025.101328
Ryan McWhorter , Salem Chouaib , Benjamin Bonavida
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 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.
{"title":"The implied dysregulated RKIP-hypoxia axis in cancer and immune evasion: Clinical implications","authors":"Ryan McWhorter , Salem Chouaib , 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":"2026-03-01","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}
Pub Date : 2026-01-01Epub Date: 2025-10-28DOI: 10.1016/j.drup.2025.101319
Shen-nan Shi , Qiuyang Xu , Zhiqi Liao , Wenjian Gong , Yilin Cui , Jiahao Liu , Xiaofei Jiao , Yijie Wu , Mengshi Luo , Yuewen Zhang , Linghui Wang , Yuanjia Wen , Wen Pan , Xuejiao Zhao , Marilyne Labrie , Zhiyong Ding , Gordon B. Mills , Ding Ma , Guang-Nian Zhao , Qinglei Gao , Yong Fang
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, in vitro and in vivo 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.
{"title":"ZBP1 antagonizes MRE11-mediated DNA end resection and confers synthetic lethality to PARP inhibition in ovarian cancer","authors":"Shen-nan Shi , Qiuyang Xu , Zhiqi Liao , Wenjian Gong , Yilin Cui , Jiahao Liu , Xiaofei Jiao , Yijie Wu , Mengshi Luo , Yuewen Zhang , Linghui Wang , Yuanjia Wen , Wen Pan , Xuejiao Zhao , Marilyne Labrie , Zhiyong Ding , Gordon B. Mills , Ding Ma , Guang-Nian Zhao , Qinglei Gao , 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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-11-04DOI: 10.1016/j.drup.2025.101323
Cheng Li , Wei Xiong , Jiahao Liu , Ke Li , Haoxiang Wang , Zhengxiang Wang , Feiyu Liu , Jianliang Shen , Zaigang Zhou , Shenpeng Ying , Long Wang
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 in vitro and in vivo. 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.
{"title":"Nanoparticles-mediated mitochondrial relocation of lipid-lowering drugs shape energy metabolism to conquer acquired immune resistance","authors":"Cheng Li , Wei Xiong , Jiahao Liu , Ke Li , Haoxiang Wang , Zhengxiang Wang , Feiyu Liu , Jianliang Shen , Zaigang Zhou , Shenpeng Ying , 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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-11-05DOI: 10.1016/j.drup.2025.101322
Yixiao Song , Zifan Ye , Yipeng Wang
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.
{"title":"Metabolite-driven reprogramming of bacterial persisters: Mechanisms and therapeutic opportunities for overcoming antibiotic tolerance","authors":"Yixiao Song , Zifan Ye , 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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-11-12DOI: 10.1016/j.drup.2025.101326
Alaa Elmetwalli
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.
{"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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-11-22DOI: 10.1016/j.drup.2025.101329
Wei Gao , Jianliang Huang , Kun Deng , Xiang Lin , Xinmiao Long , Xuetong Li , Meng Huang , Xiangyu Wang , Xiaoling She , Qing Liu , Minghua Wu
Aims
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.
Methods
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.
Results
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.
Conclusion
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.
{"title":"Endothelial cells sense temozolomide resistance to facilitate monocyte-derived macrophage infiltration in glioblastoma","authors":"Wei Gao , Jianliang Huang , Kun Deng , Xiang Lin , Xinmiao Long , Xuetong Li , Meng Huang , Xiangyu Wang , Xiaoling She , Qing Liu , 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":"2026-01-01","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}
Pub Date : 2026-01-01Epub Date: 2025-09-29DOI: 10.1016/j.drup.2025.101313
Yu-Ze Wang , Ning Gao , Zhanwen Lin , Si-Heng Wang , Shichang Ai , Zhanqi Wei , Shuishen Zhang , Junchao Cai , Weixiong Yang , Si-Cong Ma , Chao Cheng
<div><h3>Aims</h3><div>Prognostic and predictive biomarkers are two common biomarker types in clinics, with the former indicating the natural course of cancer regardless of treatment, and the latter determining the response to a specific regimen. Understanding the predictive versus prognostic effect of biomarkers is essential to understand treatment-specific response from the inherent prognosis of cancer. Herein, we aimed to uncover the predictive metabolic signatures specific to immunotherapy resistance by distinguishing the predictive versus prognostic effect of transcriptional programs in advanced non-small cell lung cancer (NSCLC) treated with immunotherapy.</div></div><div><h3>Methods</h3><div>Clinical and transcriptomic data were collected from two randomized controlled trials, OAK (n = 699, discovery cohort) and POPLAR (n = 192, validation cohort) comparing immunotherapy with chemotherapy. Metabolic transcriptional signature scores were calculated through gene set variation analysis. Cox regression and interaction test were conducted to differentiate the predictive versus prognostic effect. Additionally, lung tumor-bearing murine models were established using <em>Slc22a5</em>-overexpressing (OE) and control Lewis Lung Carcinoma (LLC) cells, and treated with immunotherapy or chemotherapy. The translational potential of an SLC22A5 (Solute Carrier Family 22 Member 5) inhibitor in combination with immunotherapy was assessed in preclinical setting. The tumor microenvironment was analyzed by flow cytometry, immunofluorescence, and Enzyme-Linked Immunosorbent Assay (ELISA) to validate the mechanistic findings.</div></div><div><h3>Results</h3><div>Metabolic transcriptional programs were divided into four categories based on different predictive effects specific to immunotherapy or chemotherapy, among which carnitine metabolism stood out as the most prominent metabolic process contributing to the resistance to immunotherapy. Specifically, SLC22A5 as the only high-affinity carnitine transporter was remarkably upregulated in immunotherapy-resistant patients. The predictive effect of SLC22A5-centric carnitine metabolism for resistance to immunotherapy rather than chemotherapy was independently validated in an external randomized trial. Critically, preclinical models revealed that <em>Slc22a5</em> overexpression drove resistance to immunotherapy but not chemotherapy, by fostering an immunosuppressive microenvironment characterized by M2 macrophage accumulation and CD8 + T cell exclusion. Furthermore, pharmacological inhibition of SLC22A5 by meldonium reshaped the tumor microenvironment toward a more inflamed state and re-sensitized resistant tumors to immunotherapy.</div></div><div><h3>Conclusions</h3><div>Our study elucidates the predictive versus prognostic effect of metabolic pathways in advanced NSCLC under immunotherapy. Tumor-intrinsic carnitine metabolism may predict and drive immunotherapy resistance, and targeting SLC22A5-mediated carnitine me
{"title":"Dissection of immunotherapeutic predictive versus prognostic transcriptional programs identifies SLC22A5-centric carnitine metabolism-driven resistance to anti-PD-(L)1 treatment in non-small cell lung cancer","authors":"Yu-Ze Wang , Ning Gao , Zhanwen Lin , Si-Heng Wang , Shichang Ai , Zhanqi Wei , Shuishen Zhang , Junchao Cai , Weixiong Yang , Si-Cong Ma , Chao Cheng","doi":"10.1016/j.drup.2025.101313","DOIUrl":"10.1016/j.drup.2025.101313","url":null,"abstract":"<div><h3>Aims</h3><div>Prognostic and predictive biomarkers are two common biomarker types in clinics, with the former indicating the natural course of cancer regardless of treatment, and the latter determining the response to a specific regimen. Understanding the predictive versus prognostic effect of biomarkers is essential to understand treatment-specific response from the inherent prognosis of cancer. Herein, we aimed to uncover the predictive metabolic signatures specific to immunotherapy resistance by distinguishing the predictive versus prognostic effect of transcriptional programs in advanced non-small cell lung cancer (NSCLC) treated with immunotherapy.</div></div><div><h3>Methods</h3><div>Clinical and transcriptomic data were collected from two randomized controlled trials, OAK (n = 699, discovery cohort) and POPLAR (n = 192, validation cohort) comparing immunotherapy with chemotherapy. Metabolic transcriptional signature scores were calculated through gene set variation analysis. Cox regression and interaction test were conducted to differentiate the predictive versus prognostic effect. Additionally, lung tumor-bearing murine models were established using <em>Slc22a5</em>-overexpressing (OE) and control Lewis Lung Carcinoma (LLC) cells, and treated with immunotherapy or chemotherapy. The translational potential of an SLC22A5 (Solute Carrier Family 22 Member 5) inhibitor in combination with immunotherapy was assessed in preclinical setting. The tumor microenvironment was analyzed by flow cytometry, immunofluorescence, and Enzyme-Linked Immunosorbent Assay (ELISA) to validate the mechanistic findings.</div></div><div><h3>Results</h3><div>Metabolic transcriptional programs were divided into four categories based on different predictive effects specific to immunotherapy or chemotherapy, among which carnitine metabolism stood out as the most prominent metabolic process contributing to the resistance to immunotherapy. Specifically, SLC22A5 as the only high-affinity carnitine transporter was remarkably upregulated in immunotherapy-resistant patients. The predictive effect of SLC22A5-centric carnitine metabolism for resistance to immunotherapy rather than chemotherapy was independently validated in an external randomized trial. Critically, preclinical models revealed that <em>Slc22a5</em> overexpression drove resistance to immunotherapy but not chemotherapy, by fostering an immunosuppressive microenvironment characterized by M2 macrophage accumulation and CD8 + T cell exclusion. Furthermore, pharmacological inhibition of SLC22A5 by meldonium reshaped the tumor microenvironment toward a more inflamed state and re-sensitized resistant tumors to immunotherapy.</div></div><div><h3>Conclusions</h3><div>Our study elucidates the predictive versus prognostic effect of metabolic pathways in advanced NSCLC under immunotherapy. Tumor-intrinsic carnitine metabolism may predict and drive immunotherapy resistance, and targeting SLC22A5-mediated carnitine me","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101313"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145221841","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 : 2026-01-01Epub Date: 2025-09-08DOI: 10.1016/j.drup.2025.101298
Zizheng Dong , Xiuzhen Fan , JoAnne J Babula , Shaobo Zhang , Jing-Yuan Liu , Jian-Ting Zhang
ABCG2 has been associated with multidrug resistance (MDR) and protection of cancer stem cells. ABCG2 knockout had no apparent adverse effect on mice. Thus, ABCG2 is an interesting and perhaps an ideal target for drug discovery to overcome MDR and eliminate cancer stem cells. Although many ABCG2 inhibitors have been identified, few have moved into clinical testing and none has been approved. Thus, there is an unmet need for novel ABCG2 inhibitors. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTAC) and molecular-glues have been gaining traction with many in clinical trials, representing a new way targeting cytosolic proteins. However, TPD agents for membrane proteins are scarce. Recently, ABCG2 inhibitors with dynamic properties have been identified that they not only inhibit ABCG2 activity but also induce ABCG2 degradation. These dynamic inhibitors are unique and may represent a new class of TPD agents for membrane proteins and next generation inhibitors for development. Here, we investigated the mechanism of action of the dynamic inhibitor PZ-39 and its analogue PZ-39C8 and showed that they selectively bound to the extracellular loop between TM5-TM6 of ABCG2. This binding induces clathrin-dependent endocytosis of mature ABCG2 and hijacks nascent ABCG2, targeting them to lysosome via autophagy for degradation. PZ-39 also effectively induced ABCG2 loss and sensitized doxorubicin resistance in xenograft tumors. Thus, further investigation of dynamic ABCG2 inhibitors may lead to the next generation of therapeutics to overcome MDR in cancer chemotherapy and contribute to future design of TPD agents targeting membrane proteins.
{"title":"Overcoming multidrug resistance using small molecule dynamic inhibitors by hijacking nascent and inducing turnover of mature ABCG2 for degradation in lysosomes","authors":"Zizheng Dong , Xiuzhen Fan , JoAnne J Babula , Shaobo Zhang , Jing-Yuan Liu , Jian-Ting Zhang","doi":"10.1016/j.drup.2025.101298","DOIUrl":"10.1016/j.drup.2025.101298","url":null,"abstract":"<div><div>ABCG2 has been associated with multidrug resistance (MDR) and protection of cancer stem cells. ABCG2 knockout had no apparent adverse effect on mice. Thus, ABCG2 is an interesting and perhaps an ideal target for drug discovery to overcome MDR and eliminate cancer stem cells. Although many ABCG2 inhibitors have been identified, few have moved into clinical testing and none has been approved. Thus, there is an unmet need for novel ABCG2 inhibitors. Targeted protein degradation (TPD) using proteolysis-targeting chimeras (PROTAC) and molecular-glues have been gaining traction with many in clinical trials, representing a new way targeting cytosolic proteins. However, TPD agents for membrane proteins are scarce. Recently, ABCG2 inhibitors with dynamic properties have been identified that they not only inhibit ABCG2 activity but also induce ABCG2 degradation. These dynamic inhibitors are unique and may represent a new class of TPD agents for membrane proteins and next generation inhibitors for development. Here, we investigated the mechanism of action of the dynamic inhibitor PZ-39 and its analogue PZ-39C8 and showed that they selectively bound to the extracellular loop between TM5-TM6 of ABCG2. This binding induces clathrin-dependent endocytosis of mature ABCG2 and hijacks nascent ABCG2, targeting them to lysosome via autophagy for degradation. PZ-39 also effectively induced ABCG2 loss and sensitized doxorubicin resistance in xenograft tumors. Thus, further investigation of dynamic ABCG2 inhibitors may lead to the next generation of therapeutics to overcome MDR in cancer chemotherapy and contribute to future design of TPD agents targeting membrane proteins.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"84 ","pages":"Article 101298"},"PeriodicalIF":21.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145050622","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}
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