Drug Resistance Updates最新文献

{"title":"Methotrexate resistance and its regulatory mechanisms in pediatric tumors and beyond","authors":"Jing Nie ,&nbsp;Lantian Huang ,&nbsp;Yan Shen ,&nbsp;Hongai Pan ,&nbsp;Siwan Wang ,&nbsp;Huawei Zhao ,&nbsp;Peng Gao ,&nbsp;Jufei Yang ,&nbsp;Xiaojun Huang ,&nbsp;Su Zeng ,&nbsp;Jing Miao","doi":"10.1016/j.drup.2025.101225","DOIUrl":"10.1016/j.drup.2025.101225","url":null,"abstract":"<div><div>Methotrexate (MTX) is a critical antimetabolite drug in treating various pediatric diseases, including acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), brain tumors, osteosarcoma, inflammatory myofibroblastic tumor (IMT), juvenile scleroderma (JS), and juvenile idiopathic arthritis (JIA). MTX acts as a folate antagonist by inhibiting dihydrofolate reductase (DHFR), an enzyme essential for the synthesis of tetrahydrofolate. This disruption impairs DNA synthesis, repair, and cellular replication, particularly affecting rapidly dividing cells. Despite its efficacy, MTX resistance poses significant challenges, particularly in pediatric oncology, where it undermines the ability to achieve sustained therapeutic effects, resulting in reduced therapeutic efficacy and poor prognosis. The mechanisms of MTX resistance encompassed reduced enzyme activity pivotal for MTX metabolism, enhanced expression of efflux transporters, genetic variations, and alterations in signaling pathways. Multifaceted strategies have been explored to overcome MTX resistance. Combination therapies with ginger extract, gold nanoparticles, and arsenic trioxide (ATO) have been investigated to augment MTX’s cytotoxic effects. Synergies with mTOR inhibitors and MDM2 inhibitors have demonstrated enhanced outcomes in ALL. In JIA, targeting ATP-binding cassette (ABC) transporters and modulating transforming growth factor‑β (TGF-β) signaling pathways have emerged as promising approaches. For osteosarcoma, emphasis on autophagy pathways and non-coding RNAs influencing chemotherapy sensitivity could enhance MTX effectiveness. This review delineates MTX's therapeutic roles, elucidates its resistance mechanisms, and discusses current and potential strategies for managing MTX resistance to bolster treatment effectiveness in pediatric tumors and other diseases. This knowledge base could underpin further research and development of personalized treatments to optimize MTX's clinical benefits.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101225"},"PeriodicalIF":15.8,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143619450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting TRAP1-dependent metabolic reprogramming to overcome doxorubicin resistance in quiescent breast cancer","authors":"Muhammad Zubair Saleem ,&nbsp;Ruyi Huang ,&nbsp;Yingying Huang ,&nbsp;Xin Guo ,&nbsp;Yang Liu ,&nbsp;Miao Gao ,&nbsp;Yinjuan Fan ,&nbsp;Zhe-Sheng Chen ,&nbsp;Zun-Fu Ke ,&nbsp;Shengnan Ye ,&nbsp;Jianhua Xu","doi":"10.1016/j.drup.2025.101226","DOIUrl":"10.1016/j.drup.2025.101226","url":null,"abstract":"<div><h3>Aims</h3><div>TRAP1 is involved in metabolic reprogramming and promotes drug resistance. We aimed to explore whether a novel HSP90 inhibitor, C210, overcomes doxorubicin (DOX) resistance of quiescent breast cancer cells by targeting TRAP1.</div></div><div><h3>Methods</h3><div>Breast cancer cells were induced to quiescence by hypoxia and low glucose. The relationship of cell metabolism with HSP90 and TRAP1 was investigated by Western blotting, ECAR, OCR, mitochondrial complex activity, and proteomic analysis. The targets of C210 and their functions were analyzed by SPR and immunoprecipitation. The antitumor effect <em>in vivo</em> was investigated with mouse tumor model.</div></div><div><h3>Results</h3><div>In hypoxia and glucose deprivation, breast cancer cells exhibited elevated TRAP1 and an OXPHOS-enhanced quiescent phenotype. These cells were highly resistant to DOX but more sensitive to C210. C210 disrupted TRAP1's interaction with OXPHOS-associated client proteins, prompting proteasome-dependent degradation of these proteins, thereby reducing OCR, mitochondrial ATP production and resulting in selective elimination of the quiescent cancer cells by inducing mitochondrial apoptosis which could be reversed by exogenous ATP. Moreover, C210 targeted glycolytic, amino acid, and β-oxidation-associated proteome. C210 demonstrated promising <em>in vivo</em> anticancer efficacy which was particularly related to OXPHOS inhibition.</div></div><div><h3>Conclusions</h3><div>C210 eliminates DOX-resistant quiescent breast cancer cells by targeting TRAP1-dependent bioenergetics.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101226"},"PeriodicalIF":15.8,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143611105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma","authors":"Zhongyan Zhang ,&nbsp;Qi Zhou ,&nbsp;Zhenchong Li ,&nbsp;Fuxin Huang ,&nbsp;Ke Mo ,&nbsp;Cheng Shen ,&nbsp;Xing Niu ,&nbsp;Baohua Hou ,&nbsp;Chuanzhao Zhang ,&nbsp;Shanzhou Huang","doi":"10.1016/j.drup.2025.101224","DOIUrl":"10.1016/j.drup.2025.101224","url":null,"abstract":"<div><h3>Aims</h3><div>Emerging resistance to Lenvatinib, which is used as a first-line agent for the treatment of advanced hepatocellular carcinoma (HCC), is still a concern. The aim of this study was to determine core factors of Lenvatinib resistance (LR) and their underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>CRISPR screening in HCC cells was conducted, which identified E3 ubiquitin ligase deltex 2 (DTX2) as a core LR-related gene. <em>In vivo</em> and <em>in vitro</em> models were used to clarify the function of DTX2 on LR and ferroptosis. The upstream regulators and downstream effectors of DTX2 were identified, revealing its complex regulatory network.</div></div><div><h3>Results</h3><div>DTX2 promoted anti-ferroptosis in LR HCC cells via downregulating the peroxisomal β-oxidation enzyme HSD17B4. DTX2 induced the ubiquitination-mediated degradation of HSD17B4, resulting in lipid metabolism changes that were associated mainly with docosahexaenoic acid (DHA)-containing PUFAs. Notably, DHA supplements could reverse DTX2-induced anti-ferroptosis and LR. Mechanistically, we uncovered that DTX2 ubiquitinated the HSD17B4 SCP structural domain through its RING structural domain and ubiquitinated the K645 site. The upregulation of DTX2 expression was mediated by JAK2-STAT3 pathway activation. The aberrant activation of STAT3 in acquired LR promoted DTX2 transcription and negatively regulated peroxisomal β-oxidation via K48-ubiquitinated HSD17B4 and decreased DHA-phospholipids levels, leading to the suppression of Lenvatinib-induced ferroptosis in HCC.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that DTX2 attenuates Lenvatinib-induced ferroptosis by inhibiting DHA biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in HCC. The combination of DHA with Lenvatinib could be a promising therapeutic strategy for patients with LR HCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101224"},"PeriodicalIF":15.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The combination of flaxseed lignans and PD-1/ PD-L1 inhibitor inhibits breast cancer growth via modulating gut microbiome and host immunity","authors":"Hao Wu ,&nbsp;Jiena Liu ,&nbsp;Xing-Hua Zhang ,&nbsp;Shengye Jin ,&nbsp;Ping Li ,&nbsp;Huidi Liu ,&nbsp;Liuying Zhao ,&nbsp;Jianyu Wang ,&nbsp;Shilu Zhao ,&nbsp;Hong-Da Tian ,&nbsp;Jin-Ru Lai ,&nbsp;Yi Hao ,&nbsp;Gui-Rong Liu ,&nbsp;Kaijian Hou ,&nbsp;Meisi Yan ,&nbsp;Shu-Lin Liu ,&nbsp;Da Pang","doi":"10.1016/j.drup.2025.101222","DOIUrl":"10.1016/j.drup.2025.101222","url":null,"abstract":"<div><h3>Background</h3><div>Patients with breast cancer (BC) who benefit from the PD-1/PD-L1 inhibitor (PDi) is limited, necessitating novel strategies to improve immunotherapy efficacy of BC. Here we aimed to investigate the inhibitory effects of flaxseed lignans (FL) on the biological behaviors of BC and evaluate the roles of FL in enhancing the anticancer effects of PDi.</div></div><div><h3>Methods</h3><div>HPLC was used to detect the content of enterolactone (ENL), the bacterial transformation product of FL. Transcript sequencing was performed and identified CD38 as a downstream target gene of ENL. CD38-overexpressing cells were constructed and cell proliferation, colony formation, wound healing and transwell assays were used to assess the function of ENL/CD38 axis on BC cells <em>in vitro</em>. Multiplexed immunohistochemistry (mIHC) and CyTOF were used to detect the changes of the tumor immune microenvironment (TIM). 16S rDNA sequencing was used to explore the changes of gut microbiota in mice. A series of <em>in vivo</em> experiments were conducted to investigate the anticancer effects and mechanisms of FL and PDi.</div></div><div><h3>Results</h3><div>FL was converted to ENL by gut microbiota and FL administration inhibited the progression of BC. ENL inhibited the malignant behaviors of BC by downregulating CD38, a key gene associated with immunosuppression and PD-1/PD-L1 blockade resistance. The mIHC assay revealed that FL administration enhanced CD3⁺, CD4⁺ and CD8⁺ cells and reduced F4/80⁺ cells in TIM. CyTOF confirmed the regulatory effects of FL and FL in combination with PDi (FLcPDi) on TIM. In addition, 16S rDNA analysis demonstrated that FLcPDi treatment significantly elevated the abundance of <em>Akkermansia</em> and, importantly, <em>Akkermansia</em> administration enhanced the response to PDi in mice treated with antibiotics.</div></div><div><h3>Conclusions</h3><div>The FL/ENL/CD38 axis inhibited BC progression. FL enhanced the anticancer effects of PDi by modulating gut microbiota and host immunity.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"80 ","pages":"Article 101222"},"PeriodicalIF":15.8,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143551117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Resistance to immunotherapy in non-small cell lung cancer: Unraveling causes, developing effective strategies, and exploring potential breakthroughs","authors":"Shuang Dong ,&nbsp;Xiaoyu Li ,&nbsp;Qing Huang ,&nbsp;Yuanxiang Li ,&nbsp;Jinjiao Li ,&nbsp;Xianmin Zhu ,&nbsp;Chang Xue ,&nbsp;Runzhi Chen ,&nbsp;Yuan Zeng ,&nbsp;Jingyi Wu ,&nbsp;Yi Zhong ,&nbsp;Sheng Hu","doi":"10.1016/j.drup.2025.101215","DOIUrl":"10.1016/j.drup.2025.101215","url":null,"abstract":"<div><div>Over the last two decades, advancements in deciphering the intricate interactions between oncology and immunity have fueled a meteoric rise in immunotherapy for non-small cell lung cancer, typified by an explosive growth of immune checkpoint inhibitors. However, resistance to immunotherapy remains inevitable. Herein we unravel the labyrinthine mechanisms of resistance to immunotherapy, characterized by their involvement of nearly all types of cells within the body, beyond the extrinsic cancer cells, and importantly, such cells are not only (inhibitory or excitatory, or both) signal recipients but also producers, acting in a context-dependent manner. At the molecular level, these mechanisms underlie genetic and epigenetic aberrations, which are regulated by or regulate various protein kinases, growth factors, and cytokines with inherently dynamic and spatially heterogeneous properties. Additionally, macroscopic factors such as nutrition, comorbidities, and the microbiome within and around organs or tumor cells are involved. Therefore, developing therapeutic strategies combined with distinct action informed by preclinical, clinical, and real-world evidence, such as radiotherapy, chemotherapy, targeted therapy, antibody-drug conjugates, oncolytic viruses, and cell-based therapies, may stand as a judicious reality, although the ideality is to overcome resistance point-by-point through a novel drug. Notably, we highlight a realignment of treatment aims, moving the primary focus from eliminating cancer cells -- such as through chemotherapy and radiotherapy -- to promoting immune modulation and underscore the value of regulating various components within the host macro- or micro-environment, as their effects, even if seemingly minimal, can cumulatively contribute to visible clinical benefit when applied in combination with ICIs. Lastly, this review also emphasizes the current hurdles scattered throughout preclinical and clinical studies, and explores evolving directions in the landscape of immunotherapy for NSCLC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101215"},"PeriodicalIF":15.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Centromere protein U mediates the ubiquitination and degradation of RPS3 to facilitate temozolomide resistance in glioblastoma","authors":"Jinmin Sun ,&nbsp;Wenyu Zhao ,&nbsp;Lei Zhang ,&nbsp;Sicheng Wu ,&nbsp;Senrui Xue ,&nbsp;Haowei Cao ,&nbsp;Biao Xu ,&nbsp;Xinmiao Li ,&nbsp;Nan Hu ,&nbsp;Tao Jiang ,&nbsp;Yixin Xu ,&nbsp;Zhifei Wang ,&nbsp;Chao Zhang ,&nbsp;Jing Ren","doi":"10.1016/j.drup.2025.101214","DOIUrl":"10.1016/j.drup.2025.101214","url":null,"abstract":"<div><h3>Aims</h3><div>Temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma (GBM) therapy; however, resistance to TMZ remains a major obstacle in GBM treatment. The aim of this study is to elucidate the mechanisms underlying TMZ resistance and explore how to enhance the sensitivity of GBM to TMZ.</div></div><div><h3>Methods</h3><div>GBM organoids were generated from patient samples, and organoid-based TMZ sensitivity testing was performed. Transcriptome sequencing was conducted on GBM organoids, which identified Centromere protein U (CENPU) as a novel key gene mediating TMZ resistance. Histopathological assessments were carried out using immunohistochemistry (IHC) and Hematoxylin and Eosin (HE) staining. Single-cell sequencing data were utilized to determine the functional states of CENPU in GBM cells. Intracranial and subcutaneous glioma mouse models were constructed to evaluate the effect of CENPU on TMZ sensitivity. The underlying mechanisms were further investigated using immunofluorescence, lentivirus transduction, co-immunoprecipitation, mass spectrometry, alkaline comet assay et al.</div></div><div><h3>Results</h3><div>CENPU was found to be highly expressed in TMZ-resistant GBM organoids and enhanced the TMZ resistance of GBM cells by promoting DNA damage repair. Its abnormal expression correlates with poor clinical outcomes in glioma patients. <em>In vivo</em> studies demonstrated that downregulation of CENPU enhances the sensitivity of GBM to TMZ. Correspondingly, rescue of CENPU expression reversed this effect on TMZ sensitivity in GBM cells. Mechanistically, CENPU cooperates with TRIM5α to promote the ubiquitination and degradation of RPS3 by inducing its polyubiquitination at the K214 residue. This process subsequently activates the ERK1/2 pathway and promotes the expression of E2F1 and RAD51. Consequently, the degradation of RPS3 and upregulation of RAD51 in GBM cells enhance DNA damage repair, thereby contributing to TMZ resistance.</div></div><div><h3>Conclusion</h3><div>Our study identified CENPU as a novel key gene mediating TMZ resistance and elucidated its molecular mechanisms, providing a new target to overcome TMZ resistance in GBM.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"80 ","pages":"Article 101214"},"PeriodicalIF":15.8,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143511427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sanfetrinem, an oral β-lactam antibiotic repurposed for the treatment of tuberculosis","authors":"Santiago Ramón-García ,&nbsp;Rubén González del Río ,&nbsp;María Pilar Arenaz-Callao ,&nbsp;Helena I. Boshoff ,&nbsp;Joaquín Rullas ,&nbsp;Sara Anca ,&nbsp;Mónica Cacho Izquierdo ,&nbsp;Esther Porras de Francisco ,&nbsp;Esther Pérez Herrán ,&nbsp;Angel Santos-Villarejo ,&nbsp;Alfonso Mendoza-Losana ,&nbsp;Santiago Ferrer-Bazaga ,&nbsp;Charles J. Thompson ,&nbsp;David Barros Aguirre ,&nbsp;Robert H. Bates","doi":"10.1016/j.drup.2025.101213","DOIUrl":"10.1016/j.drup.2025.101213","url":null,"abstract":"<div><div>Tuberculosis (TB) is historically the world’s deadliest infectious disease. New TB drugs that can avoid pre-existing resistance are desperately needed. The β-lactams are the oldest and most widely used class of antibiotics to treat bacterial infections but, for a variety of reasons, they were largely ignored until recently as a potential treatment option for TB. Recently, a growing body of evidence indicates that later-generation carbapenems in the presence of β-lactamase inhibitors could play a role in TB treatment. However, most of these drugs can only be administered intravenously in the clinic. We performed a screening of β-lactams against intracellular <em>Mycobacterium tuberculosis</em> (<em>Mtb</em>) and identified sanfetrinem cilexetil as a promising oral β-lactam candidate. Preclinical <em>in vitro</em> and <em>in vivo</em> studies demonstrated that: (i) media composition impacts the activity of sanfetrinem against <em>Mtb</em>, being more potent in the presence of physiologically relevant cholesterol as the only carbon source, compared to the standard broth media; (ii) sanfetrinem shows broad spectrum activity against <em>Mtb</em> clinical isolates, including MDR/XDR strains; (iii) sanfetrinem is rapidly bactericidal <em>in vitro</em> against <em>Mtb</em> despite being poorly stable in the assay media; (iv) there are strong <em>in vitro</em> synergistic interactions with amoxicillin, ethambutol, rifampicin and rifapentine and, (v) sanfetrinem cilexetil is active in an <em>in vivo</em> model of infection. These data, together with robust pre-clinical and clinical studies of broad-spectrum carbapenem antibiotics carried out in the 1990s by GSK, identified sanfetrinem as having potential for treating TB and catalyzed a repurposing proof-of-concept Phase 2a clinical study (NCT05388448) in South Africa.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"80 ","pages":"Article 101213"},"PeriodicalIF":15.8,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143510381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sciatic nerve stimulation enhances NK cell cytotoxicity through dopamine signaling and synergizes immunotherapy in triple-negative breast cancer","authors":"Guangqi Li ,&nbsp;Yuting Jiang ,&nbsp;Huan Tong ,&nbsp;Jifeng Liu ,&nbsp;Zedong Jiang ,&nbsp;Yunuo Zhao ,&nbsp;Keqin Tan ,&nbsp;Yu Zhang ,&nbsp;Xiaomeng Yin ,&nbsp;Hong Yun ,&nbsp;Yuxin He ,&nbsp;Hu Liao ,&nbsp;Jiangjiang Qin ,&nbsp;Xuelei Ma","doi":"10.1016/j.drup.2025.101212","DOIUrl":"10.1016/j.drup.2025.101212","url":null,"abstract":"<div><h3>Aims</h3><div>Triple-negative breast cancer (TNBC) has shown resistance to immunotherapy. Stimulating ProkR2-bearing sensory neurons of the sciatic nerve has been reported to regulate immune function by catecholamine release through the vagal-adrenal axis. We aimed to investigate the impact of sciatic nerve stimulation on anti-tumor immune responses and immunotherapy efficacy in TNBC.</div></div><div><h3>Methods</h3><div>We implemented ProkR2-bearing neuron stimulation in a TNBC mouse model. Single-cell RNA sequencing, flow cytometry, and immunohistochemistry were employed to uncover alterations in the tumor immune microenvironment. Immune cell depletion and receptor inhibitors were used to verify the cellular and molecular mechanisms by which neurostimulation regulates anti-tumor immunity.</div></div><div><h3>Results</h3><div>Sciatic nerve stimulation inhibited 4T1 tumor growth by activating natural killer (NK) cells in the tumor microenvironment. The D1-like dopamine receptor-cAMP-PKA-CREB signaling pathway is essential for enhanced NK cell cytotoxicity and tumor inhibition induced by neurostimulation. Neurostimulation upregulated tumor PD-L1 expression through IFN-gamma pathway. Combining sciatic nerve stimulation with anti-PD-1 therapy resulted in superior tumor control compared to either approach alone and demonstrated good safety.</div></div><div><h3>Conclusions</h3><div>This research addresses a long-standing gap in understanding neuro-immune regulation in cancer treatment, presenting a promising strategy for overcoming immunoresistance in TNBC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101212"},"PeriodicalIF":15.8,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143403347","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low miR-224–5p in exosomes confers colorectal cancer 5-FU resistance by upregulating S100A4","authors":"Yan-yan Yan ,&nbsp;Zhuo-fen Deng ,&nbsp;Xing-tao Wu ,&nbsp;Yu Lu ,&nbsp;Zhuang-yan Zhu ,&nbsp;Qing Wen ,&nbsp;Wei Zhang ,&nbsp;Hai-yan Zhang ,&nbsp;Xin-zhu Chen ,&nbsp;Yu-song Wu ,&nbsp;Xue-bing He ,&nbsp;Zi-ang Ma ,&nbsp;Jin-shuo Li ,&nbsp;Hong Bi ,&nbsp;Jian-ye Zhang","doi":"10.1016/j.drup.2025.101211","DOIUrl":"10.1016/j.drup.2025.101211","url":null,"abstract":"<div><div>This study aimed to identify molecular markers that mediate 5-fluorouracil (5-FU) resistance in colorectal cancer (CRC). Exosomes from 5-FU resistant CRC cells (HCT-15/FU) significantly enhanced the resistance to 5-FU and the malignant properties of HCT-15 cells. Double screening of miRNAs in CRC cell-exosomes and serum-exosomes from clinical CRC patients revealed that miR-224–5p was expressed at significantly lower levels in the 5-FU resistant type than in the 5-FU sensitive type. Moreover, the overall survival rates of 5-FU-resistant CRC patients were much lower than those of 5-FU-sensitive CRC patients. Furthermore, cellular miRNA sequencing (miR-Seq) and proteomic studies revealed that several miRNAs such as miR-224–5p, were significantly downregulated and that calcium-related proteins, including S100 calcium-binding protein A4 (S100A4), were upregulated in HCT-15/FU cells. An analysis of data from public databases revealed that patients with CRC with lower S100A4 expression had a better prognosis. In addition, miR-224–5p was shown to directly target S100A4. Functionally, <em>in vitro</em> and <em>in vivo</em> experiments verified that the downregulation of miR-224–5p promoted malignant properties and resistance to 5-FU in HCT-15 cells, whereas the upregulation of miR-224–5p in HCT-15/FU cells attenuated these effects. Notably, 5-FU combined with verapamil reversed 5-FU resistance in CRC by regulating the miR-224–5p/S100A4 pathway. Triptolide inhibited the malignant properties of HCT-15/FU cells by affecting the miR-224–5p/S100A4 axis. Overall, miR-224–5p is involved in CRC 5-FU resistance by regulating S100A4, and might serve as a molecular marker for the early prediction and intervention of 5-FU resistance in CRC patients in the clinic. Triptolide or 5-FU combined with a calcium antagonist could be used as a trial therapy for 5-FU resistant CRC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101211"},"PeriodicalIF":15.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143418563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing phytochemicals: Innovative strategies to enhance cancer immunotherapy","authors":"Qianru Zhu ,&nbsp;Ruonan Zhang ,&nbsp;Ziming Zhao ,&nbsp;Tian Xie ,&nbsp;Xinbing Sui","doi":"10.1016/j.drup.2025.101206","DOIUrl":"10.1016/j.drup.2025.101206","url":null,"abstract":"<div><div>Cancer immunotherapy has revolutionized cancer treatment, but therapeutic ineffectiveness—driven by the tumor microenvironment and immune evasion mechanisms—continues to limit its clinical efficacy. This challenge underscores the need to explore innovative approaches, such as multimodal immunotherapy. Phytochemicals, bioactive compounds derived from plants, have emerged as promising candidates for overcoming these barriers due to their immunomodulatory and antitumor properties. This review explores the synergistic potential of phytochemicals in enhancing immunotherapy by modulating immune responses, reprogramming the tumor microenvironment, and reducing immunosuppressive factors. Integrating phytochemicals with conventional immunotherapy strategies represents a novel approach to mitigating resistance and enhancing therapeutic outcomes. For instance, nab-paclitaxel has shown the potential in overcoming resistance to immune checkpoint inhibitors, while QS-21 synergistically enhances the efficacy of tumor vaccines. Furthermore, we highlight recent advancements in leveraging nanotechnology to engineer phytochemicals for improved bioavailability and targeted delivery. These innovations hold great promise for optimizing the clinical application of phytochemicals. However, further large-scale clinical studies are crucial to fully integrate these compounds into immunotherapeutic regimens effectively.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101206"},"PeriodicalIF":15.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143377648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}