Signal Transduction and Targeted Therapy最新文献

{"title":"Genetic subtype-guided immunochemotherapy in relapsed and refractory diffuse large B cell lymphoma: a phase 2 investigator-initiated nonrandomized clinical trial (GUIDANCE-06)","authors":"Yi-Ge Shen, Qing Shi, Wei Tang, Peng-Peng Xu, Yi-Wen Cao, Meng-Meng Ji, Zhong Zheng, Shu Cheng, Li Wang, Wei-Li Zhao","doi":"10.1038/s41392-025-02316-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02316-6","url":null,"abstract":"<p>Improving the outcome of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) remained an unmet need. The aim of this single-center, phase 2 trial was to evaluate the efficacy and safety of genetic subtype-guided immunochemotherapy (R-ICE-X) in patients with R/R DLBCL: R-ICE-zanubrutinib for MCD-like and BN2-like, R-ICE-lenalidomide for N1-like and NOS, R-ICE-decitabine for <i>TP53</i>^Mut, R-ICE-chidamide for EZB-like, and R-ICE-tofacitinib for ST2-like subtype. Enrolled patients were treated with assigned regimens for three cycles, and then responders were treated with autologous hematopoietic stem cell transplantation (ASCT) or 3 cycles of R-ICE-X consolidation and lenalidomide maintenance. The primary endpoint was the complete response (CR) rate. The secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety assessment. Between April 26, 2022, and July 31, 2024, 76 patients were enrolled, with 74 adhering to and 2 deviating from the protocol. Among all, the CR rate was 56.6% (95% CI, 45.2–68.0%), and the ORR was 76.3% (95% CI, 66.5–86.1%) at the end of induction. With a median follow-up of 19.5 months, the 2-year PFS rate was 69.3% (95% CI, 56.6–79.0%), and the 2-year OS rate was 88.3% (95% CI, 77.6–94.0%). The primary grade 3-4 adverse events were neutropenia (30%) and thrombocytopenia (25%). The presence of bulky disease and <i>CD70</i> mutation was linked to poor prognosis. Further gene set enrichment analysis revealed that up-regulated PI3K-AKT-mTOR signaling pathway and reduced immune cell infiltration were significantly associated with disease progression. Patients with mesenchymal or inflammatory lymphoma microenvironment subtypes benefited from R-ICE-X treatment. Our findings highlight the efficacy and safety of R-ICE-X, a mechanism-based tailored therapy, which dually targets genetic and microenvironmental alterations in R/R DLBCL.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"25 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710625","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":"Efficacy and safety of IBI351 (fulzerasib) monotherapy in KRASG12C inhibitor-naïve Chinese patients with KRASG12C-mutated metastatic colorectal cancer: a pooled analysis from phase I part of two studies","authors":"Ying Yuan, Yanhong Deng, Yongdong Jin, Zengqing Guo, Yueyin Pan, Cunji Wang, Zhiwu Wang, Yi Hu, Dong Hua, Xiangjiao Meng, Zhiye Zhang, Mingfang Zhao, Xiaorong Dong, Dingzhi Huang, Xiaoyan Li, Lian Liu, Meili Sun, Huijuan Wang, Xiuwen Wang, Nong Yang, Mingjun Zhang, Sheng Hu, Dongde Wu, Jingjing Huang, Sujie Zhang, Mengna Huang, Kefeng Ding","doi":"10.1038/s41392-025-02315-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02315-7","url":null,"abstract":"<p>IBI351 (also known as fulzerasib or GFH925), an irreversible covalent inhibitor of KRAS^G12C, has demonstrated promising anti-tumour activity in patients with solid tumours. In this study, data were pooled from the phase I part of two clinical studies (NCT05005234 and NCT05497336), aiming to evaluate the efficacy and safety of IBI351 monotherapy in KRAS^G12C inhibitor-naïve Chinese patients with <i>KRAS</i>^G12C-mutated metastatic colorectal cancer (CRC). The objective response rate (ORR) was the primary endpoint. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). As of December 13, 2023, 56 patients treated with IBI351 monotherapy were included. The median duration of treatment was 7.7 months (range: 0.3–16.7). The confirmed ORR was 44.6% (95% CI: 31.3–58.5), with a DCR of 87.5% (95% CI: 75.9–94.8). With a median follow-up of 13.8 months, the median PFS was 8.1 months (95% CI: 5.5–13.8). The median OS was 17.0 months (95% CI: 12.6–not reached). Treatment-related adverse events (TRAEs) occurred in 53 patients (94.6%), with grade 3 TRAEs in 14 patients (25.0%). No grade 4 or 5 TRAEs were observed. The most common grade 3 TRAEs were anaemia (<i>n</i> = 4, 7.1%) and gamma-glutamyltransferase increased (<i>n</i> = 3, 5.4%). TRAEs led to dose interruption in 12 patients (21.4%) and dose reduction in six patients (10.7%). No TRAEs resulted in treatment discontinuation. IBI351 demonstrated encouraging clinical efficacy and a manageable safety profile in KRAS^G12C inhibitor-naïve Chinese patients with <i>KRAS</i>^G12C-mutated metastatic CRC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701487","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":"Pseudohypoxic stabilization of HIF1α via cyclophilin D suppression promotes melanoma metastasis.","authors":"Hye-Kyung Park,Sung Hu,So Yeon Kim,Sora Yoon,Nam Gu Yoon,Ji Hye Lee,Wonyoung Choi,Sun-Young Kong,Jong Heon Kim,Dougu Nam,Byoung Heon Kang","doi":"10.1038/s41392-025-02314-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02314-8","url":null,"abstract":"Stabilization of hypoxia-inducible factor 1 alpha (HIF1α), which plays a pivotal role in regulating cellular responses to insufficient oxygen, is implicated in cancer progression, particularly epithelial-mesenchymal transition and metastatic dissemination. Despite its crucial role in tumorigenesis, the precise mechanisms governing HIF1α stabilization under varying tumor microenvironmental conditions are not fully understood. In this study, we show that stabilization of HIF1α in metastasizing melanoma under mild hypoxia is regulated primarily by mitochondrial reactive oxygen species (ROS) rather than by reduced oxygen levels. Activated HIF1α suppresses the expression of cyclophilin D (CypD), a regulator of the mitochondrial permeability transition pore (mPTP), as a reciprocal regulatory mechanism to sustain HIF1 signaling via upregulation of microRNAs miR-23a and miR-27a. Reduced expression of CypD leads to mPTP closure, resulting in elevated mitochondrial calcium accumulation and enhanced oxidative phosphorylation, which in turn increases mitochondrial ROS levels. The ROS then inhibits a prolyl hydroxylase, establishing a pseudohypoxic state that stabilizes HIF1α even in the presence of oxygen. This HIF1-reinforced and mitochondria-driven pseudohypoxic induction is essential for maintaining HIF1 signaling under conditions of mild hypoxia or transient increases in oxygen levels during melanoma metastasis. Overexpression of CypD reversed the pseudohypoxic state and potently inhibited melanoma metastasis. Thus, mitochondria-driven pseudohypoxic induction is critical for sustaining HIF1 signaling in metastasizing cancer cells and can be exploited to develop anti-metastatic therapies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"213 1","pages":"231"},"PeriodicalIF":39.3,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144693172","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":"Molecular mechanisms of unique therapeutic potential of CUDC-907 for MEF2D fusion-driven BCP-ALL.","authors":"Qing Xue,Ming Zhang,Yixiao Mo,Bo Jiao,Xuan Liu,Minghao Jiang,Yu Zhou,Yun Tan,Huimin Li,Jianming Zhang,Qianqian Zhang,Yunqi Li,Jianfeng Li,Xiaofang Ma,Duo-Hui Jing,Jian-Qing Mi,Jin Wang,Zhu Chen,Shu-Hong Shen,Sai-Juan Chen","doi":"10.1038/s41392-025-02310-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02310-y","url":null,"abstract":"MEF2D fusions are found in a special subtype of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with poor prognosis. In this study, we conducted high-throughput drug screenings using cell line and ex vivo cell model harboring, respectively, MEF2D::HNRNPUL1(MH) and MEF2D::BCL9(MB), the two major MEF2D fusions. We identified CUDC-907 as a highly potent dual-target inhibitor of PI3K/HDAC, demonstrating remarkable efficacy in inducing robust lethality while maintaining selectivity for MEF2D fusion-expressing cells. CUDC-907 effectively induced apoptosis and promoted the down-regulation of pre-BCR signaling. We discovered that the hyperactivation of the PI3K-AKT signaling pathway, HDAC9, and BCL2 contributed to the sustained state of MEF2D fusion (+) BCP-ALL. Importantly, CUDC-907 exerted dual regulatory function by targeting the integrative pathways of MEF2D fusions. It suppressed the PI3K-CREB pathway and fusion gene expression, while simultaneously inhibited transcriptional activity regulated by the MEF2D fusion-HDAC axis. CUDC-907 demonstrated remarkable efficacy in patient samples carrying distinct MEF2D fusion variants in vitro. Furthermore, this compound's effectiveness and safety were confirmed in both MH/NRASG12D BCP-ALL mouse model and MB patient-derived xenograft (PDX) model, outperforming conventional therapies. These results support the therapeutic potential of dual-pathway inhibition in MEF2D fusion (+) BCP-ALL and suggest CUDC-907 as a promising candidate for precision treatment in fusion-driven leukemias with similar molecular dependencies.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":"230"},"PeriodicalIF":39.3,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684078","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":"Aberrant Notch-signaling promotes tumor angiogenesis in esophageal squamous-cell carcinoma","authors":"Cainan Li, Pujie Wu, Xiaoting Xie, Xinjie Chen, Liping Chen, Liang Zhu, Zhixuan Xuan, Tianyuan Liu, Wen Tan, Shaosen Zhang, Dongxin Lin, Chen Wu","doi":"10.1038/s41392-025-02309-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02309-5","url":null,"abstract":"<p>Esophageal squamous-cell carcinoma (ESCC) is one of the most common gastrointestinal cancers in China, characterized by high malignancy and poor prognosis. Nowadays, the therapeutic options for this cancer are very limited. Notch-signaling is often overactivated in ESCC, but its role remains to be fully elucidated. Here, we demonstrate that aberrant Notch-signaling plays an important role in tumor angiogenesis. In clinical ESCC samples, Notch-signaling activation scores were significantly correlated with tumor microvascular density, advanced TNM stages, and short patient survival time. Silencing Notch-signaling substantially suppressed the ability of ESCC cells to promote angiogenesis in vitro and in vivo. By integrating analysis of CUT&amp;Tag and RNA sequencing data, we identified ubiquitin-specific protease 5 (USP5) as a Notch-signaling downstream effector that is transcriptionally upregulated by the NOTCH1 intracellular domain (NICD1)–RBPJ complex and mediates tumor angiogenesis. USP5 stabilized STAT3 via its deubiquitination function, thereby enhancing the production of pro-angiogenic factors by cancer cells, including VEGF, ANGPT2, and CXCL1. We showed that chemotherapy combined with the USP5 inhibitor can additionally repress tumor growth and angiogenesis in mice. These findings explain why ESCC cells have much fewer <i>NOTCH1</i> mutations than normal and precancerous epithelium, reveal a novel mechanism for Notch-signaling to drive tumor angiogenesis via the NOTCH1–USP5–STAT3 axis, and open a potential new avenue for anti-tumor angiogenesis therapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"14 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144678021","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":"Current landscape of innovative drug development and regulatory support in China","authors":"Ruirong Tan, Hua Hua, Siyuan Zhou, Zhimin Yang, Changming Yang, Guo Huang, Jin Zeng, Junning Zhao","doi":"10.1038/s41392-025-02267-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02267-y","url":null,"abstract":"<p>The global pharmaceutical landscape remains dynamic and competitive, shaped by advancements in first-in-class therapies and breakthrough technologies. The United States has maintained its leadership in first-in-class therapies and breakthrough technologies, driven by advanced regulatory pathways, significant multinational corporation investments, a robust Research and Development (R&amp;D) workforce, and continuous technological innovation. Additionally, global impact of the Food and Drug Administration (FDA) is further amplified through collaborations like Project Orbis, which facilitates simultaneous reviews of cancer treatments by multiple regulatory authorities worldwide. Europe, while historically strong, faces growing challenges in maintaining its competitive edge, particularly due to protracted regulatory timelines and complex coordination among its member states. In this competitive global environment, China has rapidly transformed from a generics-dominated market to a key player in innovative drug development. This article reviews China’s progress in innovative drug R&amp;D from 2019 to 2023, emphasizing regulatory modernization, clinical trial advancements, and the emergence of novel therapies. By comparing China’s developments with above global counterparts, this review highlights the country’s achievements in regulatory efficiency, clinical trial progress, and the development of innovative therapies such as biologics and cell and gene therapies. Through this comparative analysis, the article underscores how China’s evolving policy-driven innovation ecosystem has positioned it as a growing leader in global drug development. The review examines how enhanced regulatory efficiency, clinical trial progress, manufacturing capabilities, and international collaboration have bolstered China’s growing influence, while also discussing the future opportunities and challenges it faces in shaping global pharmaceutical innovation and development.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"31 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677961","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":"Exploratory phase II trial of an anti-PD-1 antibody camrelizumab combined with a VEGFR-2 inhibitor apatinib and chemotherapy as a neoadjuvant therapy for triple-negative breast cancer (NeoPanDa03): efficacy, safety and biomarker analysis","authors":"Xiaoxiao Liu, Chunying Zhuang, Lei Liu, Ling Xiong, Xin Xie, Ping He, Juanjuan Li, Bing Wei, Xi Yan, Tinglun Tian, Xiaorong Zhong, Jie Chen, Yan Cheng, Dan Zheng, Peng Cheng, Tianlin Sun, Weiwei Li, Changbin Zhu, Shuaitong Chen, Chao Fang, Jun Fu, Shibao Li, Jing Jing, Ting Luo","doi":"10.1038/s41392-025-02337-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02337-1","url":null,"abstract":"<p>Chemotherapy serves as the primary therapeutic approach for triple-negative breast cancer (TNBC), yet its efficacy remains unsatisfactory. This study was a single-arm, open-label, single-center clinical trial (NCT05447702) involving patients with newly diagnosed stage II-III TNBC at West China Hospital. The treatment regimen consisted of camrelizumab (200 mg intravenously every 2 weeks, 12 cycles), apatinib (250 mg orally daily), and alternating chemotherapy [nab-paclitaxel (d1, 8, 15 every 4 weeks) for 4 cycles and epirubicin plus cyclophosphamide (every 2 weeks) for 4 cycles]. From June 2023 to April 2024, 35 patients were enrolled, of whom 1 patient withdrew due to adverse reaction intolerance. At treatment completion, the total pathological complete response (tpCR, ypT0/is, ypN0) rate was 67.6% (23/34), and the breast pCR (ypT0/is) rate was 70.6% (24/34). The overall response rate following neoadjuvant treatment reached 94.1% (32/34). Elevated levels of alanine aminotransferase (38.2%) and aspartate aminotransferase (29.4%) were the most common grade 3-4 adverse events, with no significant toxicities or treatment-related deaths reported. Comprehensive analysis of serum and tissue samples collected before and after neoadjuvant therapy via Olink and RNA sequencing revealed that the treatment induced a complex systemic immune response. These findings enabled the development of two novel scoring systems: a pretreatment response predictive score system for stratification and an efficacy assessment score system for treatment response evaluation. In conclusion, camrelizumab and apatinib combined with chemotherapy have good clinical efficacy and good safety as neoadjuvant treatments for stage II-III TNBC, warranting further investigation and potential clinical application.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"14 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669692","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":"Differential expression pattern of CC chemokine receptor 7 guides precision treatment of hepatocellular carcinoma.","authors":"Jie Qin,Qianyi Gong,Cheng Zhou,Jietian Xu,Yifei Cheng,Weiyue Xu,Di Zhu,Yiming Liu,Yuye Zhang,Yanru Wang,Lingling Gao,Lanfang Li,Wulei Hou,Qian Li,Binbin Liu,Yazhen Zhu,Zuoyun Wang,Jieyi Shi,Shuangjian Qiu,Chunmin Liang","doi":"10.1038/s41392-025-02308-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02308-6","url":null,"abstract":"The treatment of hepatocellular carcinoma (HCC) faces challenges of low response rates to targeted drugs and immune checkpoint inhibitors, which are influenced by complicated microenvironment of HCC. In this study, the complex tumor microenvironment was identified by using tissue microarray (TMA), spatial transcriptomes and single-cell sequencing. High expression of CC chemokine receptor 7 (CCR7) in tumor cells predicted lower Overall Survival (OS). Conversely, CRISPR-Cas9-mediated knockout of CCR7 enhanced the sensitivity of HCC to sorafenib in preclinical experiments, resulting from the inhibition of epithelial-mesenchymal transition through the AKT and ERK signaling pathways. Simultaneously, we revealed CCR7 expression in stromal cells, with increased infiltration of CCR7+ immune cells into the tumor mesenchyme associated with high CCL21 expression at tumor sites. Subsequently, VEGF-C was identified as an independent predictor of higher patient OS and showed a significant positive correlation with CCR7 signaling. Interestingly, exogenous VEGF-C was found to promote the formation of tertiary lymphoid structures (TLSs) by activating lymphatic angiogenesis and the CCL21/CCR7 axis. As a result, VEGF-C treatment enhanced the efficacy of anti-PD-1 immunotherapy. This study highlights the opposing effects of tumor cell-derived versus stromal cell-derived CCR7 expression and guides the precision treatment for HCC.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"103 1","pages":"229"},"PeriodicalIF":39.3,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144669487","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 epigenetic regulators as a promising avenue to overcome cancer therapy resistance","authors":"Jiawei Song, Ping Yang, Canting Chen, Weiqun Ding, Olivier Tillement, Hao Bai, Shuyu Zhang","doi":"10.1038/s41392-025-02266-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02266-z","url":null,"abstract":"<p>Cancer remains one of the leading health threats globally, with therapeutic resistance being a long-standing challenge across chemotherapy, radiotherapy, targeted therapy, and immunotherapy. In recent years, the association between epigenetic modification abnormalities and therapeutic resistance in tumors has garnered widespread attention, spurring interest in the development of approaches to target epigenetic factors. In this review, we explore the widespread dysregulation and crosstalk of various types of epigenetic modifications, including DNA methylation, histone modifications, and non-coding RNA changes, which interact through complex regulatory networks in tumors. Clinically, single-targeted therapy based on epigenetic modification usually has its limited effect against cancer. However, the combination of epigenetic drugs with other treatment modalities, such as chemotherapy, targeted therapy, or immunotherapy, shows potential for synergistically enhancing efficacy and reducing drug resistance. Therefore, we evaluate the possibility and potential mechanisms of targeting epigenetic modifications to overcome resistance in cancer therapy, and discuss the challenges and opportunities in moving epigenetic therapy into clinical practice. Moreover, the application of multi-omics technologies will aid in identifying core epigenetic factors from complex epigenetic networks, enabling precision treatment and overcoming therapeutic resistance in tumors. Furthermore, the development of spatial multi-omics technologies, by providing spatial coordinates of cellular and molecular heterogeneity, revolutionizes our understanding of the tumor microenvironment, offering new perspectives for precision therapy. In summary, the combined application of epigenetic therapies and the integration of multi-omics technologies herald a new direction for cancer treatment, holding the potential to achieve more effective personalized treatment strategies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"15 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652272","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":"Phosphorylated Toll-like receptor 3 nuclear translocation in cancer cell promotes metastasis and chemoresistance","authors":"Zixin Wang, Yan Gu, Yanfang Liu, Ziqiao Wang, Xinyuan Chen, Haoze Wang, Wei Zhang, Gang Jin, Xuetao Cao","doi":"10.1038/s41392-025-02307-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02307-7","url":null,"abstract":"<p>Aberrant expression and subcellular location of innate sensors in cancer cells, such as Toll-like receptors (TLRs), correlates with pro-tumoral inflammation and cancer progression, but the mechanism is still largely unknown. Deciphering the proinflammatory mediators in tumor microenvironment will contribute to the development of cancer therapeutics. By using immunohistochemistry in pancreatic ductal adenocarcinoma (PDAC) and multiple other cancer samples, here we found that cancer cell TLR3, a well-known cytoplasmic dsRNA sensor, translocated to the nucleus especially upon chemotherapy stress. Nuclear TLR3 increased the invasive and proliferative properties, and inhibited chemotherapy-induced apoptosis of cancer cells in vitro. Meanwhile, mice bearing cancer cells with nuclear TLR3 exhibited increased liver metastasis and shortened survival. Mechanistically, phosphokinase JAK1 was responsible for TLR3 phosphorylation at S155 to induce its nuclear translocation in cooperation with a nuclear transport factor importin α5. Chemotherapeutic stress induced the aberrant aggregation of dsRNA in the nucleus, which potentially contributed to nuclear TLR3 activation. Then nuclear TLR3 recruited protein arginine methyltransferase 5 (PRMT5) and bound to c-Myc to promote symmetrical dimethylation and multimerization of c-Myc, resulting in the activation of c-Myc downstream target genes and pro-tumoral signaling pathways. Accordingly, high levels of cancer cell nuclear TLR3 in clinical samples predicted patients’ worse prognosis with shorter disease-free survival, overall survival and poor response to neoadjuvant chemotherapy. Therefore, the identification of nuclear TLR3 provides new insight into non-classical functions of innate immune sensors in cancer, and JAK1/TLR3/PRMT5/c-Myc axis may sever as a potential prognostic indicator and therapeutic target to overcome chemoresistance.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652282","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}