Pub Date : 2026-05-01Epub Date: 2026-01-31DOI: 10.1016/j.drup.2026.101363
Qingxin Chen , Jianxin Liu , Jianming Wu , Xin Xiang , Xiaogang Zhou , Jianing Mi , Jing Wei , Xiao Zou , Anguo Wu
Cellular senescence, a stress-induced state of stable cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP), plays a paradoxical role in cancer biology. On the one hand, senescent cells function as a barrier to tumor initiation by activating the DNA damage response (DDR) and tumor suppressor pathways such as p53/p21 and p16INK4a–retinoblastoma (RB). On the other hand, their long-term persistence promotes chronic inflammation, immune evasion, and tissue remodeling via sustained SASP, ultimately facilitating tumor progression, metastasis, and therapeutic resistance. This review elucidates the hallmarks of cellular senescence, explores its dual roles and mechanistic underpinnings in tumor suppression and promotion, highlighting the key molecular circuits governing the senescence phenotype, such as telomere dynamics, autophagy–lysosome function, and immunosurveillance. We further examine targeted therapeutic approaches, such as senolytics and senomorphics, and their integration into sequential induction and clearance regimens. These interventions aim to leverage the transient SASP to enhance immune recognition while minimizing the pro-tumorigenic effects associated with persistent SASP. Despite these advances, challenges such as tissue specificity, off-target effects, biomarker inconsistency, and cellular heterogeneity remain major hurdles to clinical translation. To transcend the traditional static and binary perspective of senescence, we introduce a dynamic plasticity model that conceptualizes senescence as a context-dependent and dynamically regulated program, potentially reversible and modulated by molecular switches, temporal patterns of SASP, and microenvironmental factors. Targeting these plasticity checkpoints holds promise for optimizing “one-two punch” combination regimens and expanding immunotherapeutic windows, thereby offering a novel paradigm for improving outcomes in aging-related cancers.
{"title":"Cellular senescence in cancer: Friend or fraud?","authors":"Qingxin Chen , Jianxin Liu , Jianming Wu , Xin Xiang , Xiaogang Zhou , Jianing Mi , Jing Wei , Xiao Zou , Anguo Wu","doi":"10.1016/j.drup.2026.101363","DOIUrl":"10.1016/j.drup.2026.101363","url":null,"abstract":"<div><div>Cellular senescence, a stress-induced state of stable cell cycle arrest accompanied by a senescence-associated secretory phenotype (SASP), plays a paradoxical role in cancer biology. On the one hand, senescent cells function as a barrier to tumor initiation by activating the DNA damage response (DDR) and tumor suppressor pathways such as p53/p21 and p16<sup>INK4a</sup>–retinoblastoma (RB). On the other hand, their long-term persistence promotes chronic inflammation, immune evasion, and tissue remodeling via sustained SASP, ultimately facilitating tumor progression, metastasis, and therapeutic resistance. This review elucidates the hallmarks of cellular senescence, explores its dual roles and mechanistic underpinnings in tumor suppression and promotion, highlighting the key molecular circuits governing the senescence phenotype, such as telomere dynamics, autophagy–lysosome function, and immunosurveillance. We further examine targeted therapeutic approaches, such as senolytics and senomorphics, and their integration into sequential induction and clearance regimens. These interventions aim to leverage the transient SASP to enhance immune recognition while minimizing the pro-tumorigenic effects associated with persistent SASP. Despite these advances, challenges such as tissue specificity, off-target effects, biomarker inconsistency, and cellular heterogeneity remain major hurdles to clinical translation. To transcend the traditional static and binary perspective of senescence, we introduce a dynamic plasticity model that conceptualizes senescence as a context-dependent and dynamically regulated program, potentially reversible and modulated by molecular switches, temporal patterns of SASP, and microenvironmental factors. Targeting these plasticity checkpoints holds promise for optimizing “one-two punch” combination regimens and expanding immunotherapeutic windows, thereby offering a novel paradigm for improving outcomes in aging-related cancers.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"Article 101363"},"PeriodicalIF":21.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146095690","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 : 2026-05-01Epub Date: 2026-02-04DOI: 10.1016/j.drup.2026.101373
Xiao-yu Jing, Guo-qian He, Xia Guo
{"title":"A novel frameshift mutation in a case of therapy-resistant metastatic pheochromocytoma","authors":"Xiao-yu Jing, Guo-qian He, Xia Guo","doi":"10.1016/j.drup.2026.101373","DOIUrl":"10.1016/j.drup.2026.101373","url":null,"abstract":"","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"Article 101373"},"PeriodicalIF":21.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134130","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 : 2026-05-01Epub Date: 2026-02-05DOI: 10.1016/j.drup.2026.101374
Li Jiang , Ying Bin , Yaoyi Huang , Lanhua Wu , Xingyue Qiu , Youchang Du , Jinglin Mi , Kang Liu , Yayan Deng , Jiancheng Ning , Mingxuan Li , Zhen Meng , Yating Qin , Huisi Zhang , Tianyu Wu , Ding Liang , Zuoting Cao , Min Kang
Aims
Radioresistance remains a significant challenge in nasopharyngeal carcinoma (NPC) treatment, resulting in treatment failure and poor clinical outcomes. This study aims to explore and characterize the functional significance and molecular mechanism of SPI1 (a hematopoietic lineage transcription factor) in NPC radioresistance.
Methods
RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence were performed to investigate expression of genes and proteins. Cell viability, apoptosis, migration, and tube formation were determined by MTT, flow cytometry, wound healing, transwell, and tube formation assays. Acyl Biotin Exchange (ABE) assay was used to determine palmitoylation levels of SPI1. Co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter, EMSA, and RNA pull-down were conducted to analyze the interaction between genes.
Results
SPI1 was significantly upregulated in radioresistant NPC tissues and cells, correlating with a poor prognosis. Knockdown of SPI1 suppressed radioresistance in NPC cells and enhanced tumor radiosensitivity in vivo. Palmitoylation of SPI1 at C5 inhibited E3 ubiquitin ligase casitas B-lineage lymphoma (c-CBL)-mediated ubiquitination and degradation, causing SPI1 upregulation in radioresistant NPC cells. SPI1 increased miR-205–5p expression and exosomal enrichment in radioresistant NPC cells, subsequently enhancing endothelial cell angiogenesis. Engineered exosomes carrying miR-205–5p inhibitor suppressed angiogenesis and radioresistance in xenograft models by inhibiting the WW domain-containing protein 2 (WWC2)-mediated Hippo pathway.
Conclusions
Collectively, our findings suggest that SPI1 palmitoylation inhibits c-CBL-mediated ubiquitination and degradation, thereby enhancing SPI1 protein stability and its transcriptional regulation of miR-205–5p. Upregulated miR-205–5p in NPC cells is packaged into exosomes and transferred to endothelial cells, where it targets and inhibits WWC2 expression, eventually promoting angiogenesis and NPC radioresistance.
{"title":"Palmitoylation modification of SPI1 promotes nasopharyngeal carcinoma radioresistance through inhibiting c-CBL-mediated ubiquitination and degradation","authors":"Li Jiang , Ying Bin , Yaoyi Huang , Lanhua Wu , Xingyue Qiu , Youchang Du , Jinglin Mi , Kang Liu , Yayan Deng , Jiancheng Ning , Mingxuan Li , Zhen Meng , Yating Qin , Huisi Zhang , Tianyu Wu , Ding Liang , Zuoting Cao , Min Kang","doi":"10.1016/j.drup.2026.101374","DOIUrl":"10.1016/j.drup.2026.101374","url":null,"abstract":"<div><h3>Aims</h3><div>Radioresistance remains a significant challenge in nasopharyngeal carcinoma (NPC) treatment, resulting in treatment failure and poor clinical outcomes. This study aims to explore and characterize the functional significance and molecular mechanism of SPI1 (a hematopoietic lineage transcription factor) in NPC radioresistance.</div></div><div><h3>Methods</h3><div>RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence were performed to investigate expression of genes and proteins. Cell viability, apoptosis, migration, and tube formation were determined by MTT, flow cytometry, wound healing, transwell, and tube formation assays. Acyl Biotin Exchange (ABE) assay was used to determine palmitoylation levels of SPI1. Co-immunoprecipitation, chromatin immunoprecipitation, dual-luciferase reporter, EMSA, and RNA pull-down were conducted to analyze the interaction between genes.</div></div><div><h3>Results</h3><div>SPI1 was significantly upregulated in radioresistant NPC tissues and cells, correlating with a poor prognosis. Knockdown of SPI1 suppressed radioresistance in NPC cells and enhanced tumor radiosensitivity <em>in vivo</em>. Palmitoylation of SPI1 at C5 inhibited E3 ubiquitin ligase casitas B-lineage lymphoma (c-CBL)-mediated ubiquitination and degradation, causing SPI1 upregulation in radioresistant NPC cells. SPI1 increased miR-205–5p expression and exosomal enrichment in radioresistant NPC cells, subsequently enhancing endothelial cell angiogenesis. Engineered exosomes carrying miR-205–5p inhibitor suppressed angiogenesis and radioresistance in xenograft models by inhibiting the WW domain-containing protein 2 (WWC2)-mediated Hippo pathway.</div></div><div><h3>Conclusions</h3><div>Collectively, our findings suggest that SPI1 palmitoylation inhibits c-CBL-mediated ubiquitination and degradation, thereby enhancing SPI1 protein stability and its transcriptional regulation of miR-205–5p. Upregulated miR-205–5p in NPC cells is packaged into exosomes and transferred to endothelial cells, where it targets and inhibits WWC2 expression, eventually promoting angiogenesis and NPC radioresistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"Article 101374"},"PeriodicalIF":21.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146134129","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 : 2026-05-01Epub Date: 2026-01-28DOI: 10.1016/j.drup.2026.101361
Wenjia Zhang , Junjie Ma , Yuka Yanagi , Ping Yin , Jin Cheng , Yi Wang , Nan Hong , Jens Ricke , Huadan Xue , Sihang Cheng
Cancer remains a leading cause of global mortality, with therapeutic resistance posing a formidable clinical obstacle. Inorganic nanotheranostics-multifunctional platforms integrating diagnostic and therapeutic capabilities-offer a promising strategy to overcome this barrier. This review systematically examines how distinct classes of inorganic nanomaterials (including iron, gadolinium, titanium, gold, manganese, carbon, and silicon-based systems) are engineered to counteract specific resistance mechanisms through unique physicochemical properties and biological interactions. We highlight their roles in enhancing drug delivery, modulating the tumor microenvironment, enabling precise imaging, and synergizing with various treatment modalities such as chemotherapy, radiotherapy, and immunotherapy. Advances in stimulus-responsive design, targeted delivery, and combinatorial therapies are discussed. Finally, we critically evaluate the translational challenges-including pharmacokinetics, long-term safety, and manufacturing scalability-and outline future directions toward clinically effective, personalized nanotheranostic interventions in oncology.
{"title":"Overcoming therapeutic resistance in oncology: The prospects of inorganic nanotheranostics","authors":"Wenjia Zhang , Junjie Ma , Yuka Yanagi , Ping Yin , Jin Cheng , Yi Wang , Nan Hong , Jens Ricke , Huadan Xue , Sihang Cheng","doi":"10.1016/j.drup.2026.101361","DOIUrl":"10.1016/j.drup.2026.101361","url":null,"abstract":"<div><div>Cancer remains a leading cause of global mortality, with therapeutic resistance posing a formidable clinical obstacle. Inorganic nanotheranostics-multifunctional platforms integrating diagnostic and therapeutic capabilities-offer a promising strategy to overcome this barrier. This review systematically examines how distinct classes of inorganic nanomaterials (including iron, gadolinium, titanium, gold, manganese, carbon, and silicon-based systems) are engineered to counteract specific resistance mechanisms through unique physicochemical properties and biological interactions. We highlight their roles in enhancing drug delivery, modulating the tumor microenvironment, enabling precise imaging, and synergizing with various treatment modalities such as chemotherapy, radiotherapy, and immunotherapy. Advances in stimulus-responsive design, targeted delivery, and combinatorial therapies are discussed. Finally, we critically evaluate the translational challenges-including pharmacokinetics, long-term safety, and manufacturing scalability-and outline future directions toward clinically effective, personalized nanotheranostic interventions in oncology.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"Article 101361"},"PeriodicalIF":21.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071803","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}
Herpes simplex virus type 1 (HSV-1) infects approximately four billion people worldwide, and the emergence of drug-resistant strains has reduced the effectiveness of existing antivirals. Targeting host pathways exploited by HSV-1 represents an attractive strategy for developing resistance-refractory antivirals.
Methods
We evaluated the antiviral potential of doxorubicin, an FDA-approved anticancer drug, against HSV-1 using in vitro cell culture systems, an ex vivo porcine corneal model, and an in vivo murine ocular infection model. Viral replication, host signaling pathways, and combinatorial interactions with nucleoside analogs were systematically assessed.
Results
Doxorubicin potently inhibited HSV-1 replication at sub-cytotoxic concentrations by suppressing the host PI3K-AKT-mTOR signaling axis, a pathway required for viral entry and productive replication. Antiviral activity was observed against laboratory-adapted strains as well as clinical acyclovir-resistant HSV-1 isolates. Pharmacological modulation of PI3K-AKT signaling, pathway activation kinetics, and studies in doxorubicin-resistant cells confirmed a host-directed mechanism. Doxorubicin exhibited strong synergy with nucleoside analog antivirals, enabling dose reduction without loss of efficacy. While inhibition of PI3K-AKT signaling constrained productive replication of both wild-type and oncolytic HSV-1, these effects were context-dependent and relevant to therapeutic settings that rely on robust viral replication.
Conclusions
This study identifies PI3K-AKT pathway inhibition as a novel host-directed antiviral mechanism underlying doxorubicin’s activity against HSV-1, demonstrates its synergistic potential with nucleoside analogs, and provides mechanistic insight into raising concerns over oncolytic HSV-based therapies. Collectively, these findings highlight the potential of localized, host-targeted strategies for managing drug-resistant HSV-1 infections.
{"title":"Host-directed novel mechanistic insights of doxorubicin reveal its efficacy against drug-resistant HSV-1 underscoring risks with oncolytic virotherapy","authors":"Pankaj Sharma , Divya Kapoor , Sudhanshu Kumar Singh , Xiang Shen , Chandrashekhar D. Patil , Deepak Shukla","doi":"10.1016/j.drup.2026.101362","DOIUrl":"10.1016/j.drup.2026.101362","url":null,"abstract":"<div><h3>Background</h3><div>Herpes simplex virus type 1 (HSV-1) infects approximately four billion people worldwide, and the emergence of drug-resistant strains has reduced the effectiveness of existing antivirals. Targeting host pathways exploited by HSV-1 represents an attractive strategy for developing resistance-refractory antivirals.</div></div><div><h3>Methods</h3><div>We evaluated the antiviral potential of doxorubicin, an FDA-approved anticancer drug, against HSV-1 using <em>in vitro</em> cell culture systems, an <em>ex vivo</em> porcine corneal model, and an <em>in vivo</em> murine ocular infection model. Viral replication, host signaling pathways, and combinatorial interactions with nucleoside analogs were systematically assessed.</div></div><div><h3>Results</h3><div>Doxorubicin potently inhibited HSV-1 replication at sub-cytotoxic concentrations by suppressing the host PI3K-AKT-mTOR signaling axis, a pathway required for viral entry and productive replication. Antiviral activity was observed against laboratory-adapted strains as well as clinical acyclovir-resistant HSV-1 isolates. Pharmacological modulation of PI3K-AKT signaling, pathway activation kinetics, and studies in doxorubicin-resistant cells confirmed a host-directed mechanism. Doxorubicin exhibited strong synergy with nucleoside analog antivirals, enabling dose reduction without loss of efficacy. While inhibition of PI3K-AKT signaling constrained productive replication of both wild-type and oncolytic HSV-1, these effects were context-dependent and relevant to therapeutic settings that rely on robust viral replication.</div></div><div><h3>Conclusions</h3><div>This study identifies PI3K-AKT pathway inhibition as a novel host-directed antiviral mechanism underlying doxorubicin’s activity against HSV-1, demonstrates its synergistic potential with nucleoside analogs, and provides mechanistic insight into raising concerns over oncolytic HSV-based therapies. Collectively, these findings highlight the potential of localized, host-targeted strategies for managing drug-resistant HSV-1 infections.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"Article 101362"},"PeriodicalIF":21.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071802","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 : 2026-05-01Epub Date: 2026-02-08DOI: 10.1016/j.drup.2026.101375
Jiajing Luo , Han Zhuo , Minghui Zheng , Yi Fang , Xuran Wang , Yangyang Jin , Yaoyao Li , Siyu Du , Jie Wang , Cailin Xue , Runqiu Jiang , Gang Li
Objective
To investigate the role and molecular mechanism of the E3 ubiquitin ligase RNF26 in regulating the immunogenicity of hepatocellular carcinoma (HCC).
Methods
We integrated multi-omics analyses of clinical HCC specimens with different immunogenicity, established HCC models using hepatocyte-specific Rnf26 knockout mice, and employed in vitro 3D tumor-T cell co-culture systems, RNA-seq, molecular interaction assays, and pharmacological inhibition to systematically examine RNF26's regulation of T cell function, antigen presentation, and endoplasmic reticulum (ER) stress.
Results
RNF26 was highly expressed in immune-"cold" HCC, and its transcription was directly regulated by the inflammatory JAK-STAT3 axis. In HCC cells, RNF26 degraded the ER chaperone GRP78 via K48-linked polyubiquitination, inducing sustained ER stress. This resulted in diminished MHC-I antigen presentation and increased PD-L1 expression. This mechanism consistently inhibited CD8+ T cell infiltration, promoted T cell exhaustion, and drove immune evasion in both in vivo and in vitro models. Inhibiting ER stress reversed the RNF26-mediated immunosuppressive phenotype.
Conclusion
RNF26 is a pivotal molecular node linking the inflammatory microenvironment to immune suppression in HCC. By ubiquitinating and degrading GRP78 to instigate ER stress, it dually regulates antigen presentation and immune checkpoint expression. Targeting the RNF26-GRP78 axis represents a promising novel strategy for reversing HCC immune resistance and enhancing the efficacy of immunotherapy.
{"title":"RNF26 regulating tumor immunogenicity of hepatocellular carcinoma by degrading GRP78 and instigating ER stress","authors":"Jiajing Luo , Han Zhuo , Minghui Zheng , Yi Fang , Xuran Wang , Yangyang Jin , Yaoyao Li , Siyu Du , Jie Wang , Cailin Xue , Runqiu Jiang , Gang Li","doi":"10.1016/j.drup.2026.101375","DOIUrl":"10.1016/j.drup.2026.101375","url":null,"abstract":"<div><h3>Objective</h3><div>To investigate the role and molecular mechanism of the E3 ubiquitin ligase RNF26 in regulating the immunogenicity of hepatocellular carcinoma (HCC).</div></div><div><h3>Methods</h3><div>We integrated multi-omics analyses of clinical HCC specimens with different immunogenicity, established HCC models using hepatocyte-specific <em>Rnf26</em> knockout mice, and employed <em>in vitro</em> 3D tumor-T cell co-culture systems, RNA-seq, molecular interaction assays, and pharmacological inhibition to systematically examine RNF26's regulation of T cell function, antigen presentation, and endoplasmic reticulum (ER) stress.</div></div><div><h3>Results</h3><div>RNF26 was highly expressed in immune-\"cold\" HCC, and its transcription was directly regulated by the inflammatory JAK-STAT3 axis. In HCC cells, RNF26 degraded the ER chaperone GRP78 via K48-linked polyubiquitination, inducing sustained ER stress. This resulted in diminished MHC-I antigen presentation and increased PD-L1 expression. This mechanism consistently inhibited CD8<sup>+</sup> T cell infiltration, promoted T cell exhaustion, and drove immune evasion in both <em>in vivo</em> and <em>in vitro</em> models. Inhibiting ER stress reversed the RNF26-mediated immunosuppressive phenotype.</div></div><div><h3>Conclusion</h3><div>RNF26 is a pivotal molecular node linking the inflammatory microenvironment to immune suppression in HCC. By ubiquitinating and degrading GRP78 to instigate ER stress, it dually regulates antigen presentation and immune checkpoint expression. Targeting the RNF26-GRP78 axis represents a promising novel strategy for reversing HCC immune resistance and enhancing the efficacy of immunotherapy.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"Article 101375"},"PeriodicalIF":21.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146138432","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 : 2026-03-17DOI: 10.1016/j.drup.2026.101391
Beata Kruszewska-Naczk, Natalia Burzyńska, Dominika Goik, Mariusz Grinholc, Joanna Nakonieczna, Natalia Pawlik, Michał K Pieranski, Agata Wozniak-Pawlikowska, Aleksandra Rapacka-Zdonczyk, Tianhong Dai
Antimicrobial blue light (aBL) is emerging as a promising non-pharmacological antimicrobial strategy with multitarget activity and a low risk of resistance development. Its effects are primarily mediated by endogenous porphyrins, but additional chromophores such as flavins and bacterial pigments can also contribute. In this review, we summarize current evidence on these photosensitizers and discuss how their diversity underlies species-dependent susceptibility, with special emphasis on the variable responses of Streptococcus and Enterococcus spp. At the molecular level, aBL-induced reactive oxygen species (ROS) damage DNA, proteins, and membranes, disrupting metabolic pathways, efflux pumps, and membrane integrity. Genetic determinants, including porphyrin biosynthesis genes, cell envelope regulators, and components of the SOS and oxidative stress responses, further influence susceptibility. Transcriptomic studies reveal global shifts affecting stress responses, energy metabolism, motility, membrane remodeling, metal ion regulation, and virulence-associated functions. Additional microbial determinants, such as biofilm formation, virulence factors, and antibiotic resistance profiles, modulate treatment outcomes, while environmental and physiological parameters (growth phase, inoculum density, temperature, wavelength, and irradiance) strongly impact efficacy. Altogether, these findings indicate that aBL efficacy is shaped by a complex interplay of chromophore availability, genetic background, physiological state, and external conditions. Clarifying these mechanisms is essential to optimize aBL for clinical and industrial applications. In summary, this review provides a comprehensive overview of the molecular and physiological bases of bacterial susceptibility to aBL and outlines key gaps that must be addressed to translate this modality into routine antimicrobial practice.
{"title":"Mechanisms and determinants of bacterial susceptibility to antimicrobial Blue Light: From chromophores to transcriptomes.","authors":"Beata Kruszewska-Naczk, Natalia Burzyńska, Dominika Goik, Mariusz Grinholc, Joanna Nakonieczna, Natalia Pawlik, Michał K Pieranski, Agata Wozniak-Pawlikowska, Aleksandra Rapacka-Zdonczyk, Tianhong Dai","doi":"10.1016/j.drup.2026.101391","DOIUrl":"https://doi.org/10.1016/j.drup.2026.101391","url":null,"abstract":"<p><p>Antimicrobial blue light (aBL) is emerging as a promising non-pharmacological antimicrobial strategy with multitarget activity and a low risk of resistance development. Its effects are primarily mediated by endogenous porphyrins, but additional chromophores such as flavins and bacterial pigments can also contribute. In this review, we summarize current evidence on these photosensitizers and discuss how their diversity underlies species-dependent susceptibility, with special emphasis on the variable responses of Streptococcus and Enterococcus spp. At the molecular level, aBL-induced reactive oxygen species (ROS) damage DNA, proteins, and membranes, disrupting metabolic pathways, efflux pumps, and membrane integrity. Genetic determinants, including porphyrin biosynthesis genes, cell envelope regulators, and components of the SOS and oxidative stress responses, further influence susceptibility. Transcriptomic studies reveal global shifts affecting stress responses, energy metabolism, motility, membrane remodeling, metal ion regulation, and virulence-associated functions. Additional microbial determinants, such as biofilm formation, virulence factors, and antibiotic resistance profiles, modulate treatment outcomes, while environmental and physiological parameters (growth phase, inoculum density, temperature, wavelength, and irradiance) strongly impact efficacy. Altogether, these findings indicate that aBL efficacy is shaped by a complex interplay of chromophore availability, genetic background, physiological state, and external conditions. Clarifying these mechanisms is essential to optimize aBL for clinical and industrial applications. In summary, this review provides a comprehensive overview of the molecular and physiological bases of bacterial susceptibility to aBL and outlines key gaps that must be addressed to translate this modality into routine antimicrobial practice.</p>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"101391"},"PeriodicalIF":21.7,"publicationDate":"2026-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147492014","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: 2025-11-28DOI: 10.1016/j.drup.2025.101330
Yuqing Wang , Min Deng , Haipeng Lei , Kai Miao , Xiaodong Shu , Jianjie Li , Dongyang Tang , Yangyang Feng , Sek Man Su , Ling Li , Yanjie Wang , Heng Sun , Fangyuan Shao , Tingting An , Xiaoling Li , Fanlin Zhou , Tingxiu Xiang , Xiaoling Xu , Chuxia Deng
Platinum-based chemotherapy remains a cornerstone of cancer treatment; however, its clinical efficacy is frequently compromised by acquired drug resistance. Our study elucidated a novel resistance mechanism mediated by LARS2 signaling in mammary tumors. Through comprehensive multi-omics analyses of cancer patients, mouse models, and functional validation, we demonstrated that platinum treatment upregulates LARS2 via a danger-triggered host response during resistant tumor progression, concomitant with increased chromatin accessibility. This signaling drives drug resistance through two key mechanisms: enrichment of cancer stem cells and promotion of TGF-β-mediated immunosuppression, as evidenced by M2 macrophage polarization and CD8+ T cell exhaustion. Importantly, we developed an effective therapeutic strategy combining carboplatin with LARS2 signaling pathway inhibition, which successfully reversed platinum resistance and restored PD-1 checkpoint blockade sensitivity in preclinical models. These findings not only advance our understanding of chemotherapy resistance, but also provide a translatable therapeutic framework for breast cancer and other platinum-treated malignancies.
{"title":"Lars2-signaling mediates platinum resistance by accumulating cancer stem cell population and suppressing anti-tumor immunity","authors":"Yuqing Wang , Min Deng , Haipeng Lei , Kai Miao , Xiaodong Shu , Jianjie Li , Dongyang Tang , Yangyang Feng , Sek Man Su , Ling Li , Yanjie Wang , Heng Sun , Fangyuan Shao , Tingting An , Xiaoling Li , Fanlin Zhou , Tingxiu Xiang , Xiaoling Xu , Chuxia Deng","doi":"10.1016/j.drup.2025.101330","DOIUrl":"10.1016/j.drup.2025.101330","url":null,"abstract":"<div><div>Platinum-based chemotherapy remains a cornerstone of cancer treatment; however, its clinical efficacy is frequently compromised by acquired drug resistance. Our study elucidated a novel resistance mechanism mediated by LARS2 signaling in mammary tumors. Through comprehensive multi-omics analyses of cancer patients, mouse models, and functional validation, we demonstrated that platinum treatment upregulates LARS2 via a danger-triggered host response during resistant tumor progression, concomitant with increased chromatin accessibility. This signaling drives drug resistance through two key mechanisms: enrichment of cancer stem cells and promotion of TGF-β-mediated immunosuppression, as evidenced by M2 macrophage polarization and CD8<sup>+</sup> T cell exhaustion. Importantly, we developed an effective therapeutic strategy combining carboplatin with LARS2 signaling pathway inhibition, which successfully reversed platinum resistance and restored PD-1 checkpoint blockade sensitivity in preclinical models. These findings not only advance our understanding of chemotherapy resistance, but also provide a translatable therapeutic framework for breast cancer and other platinum-treated malignancies.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101330"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145613764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号