Signal Transduction and Targeted Therapy最新文献

{"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":"Phosphoglycerate dehydrogenase stabilizes protein kinase C delta type mRNA to promote hepatocellular carcinoma progression","authors":"Bin Cheng, Pai Peng, Shi Chen, Rui Liu, Xiaosong Li, Ke Wang, Jing Ma, Kai Wang, Ni Tang, Ailong Huang","doi":"10.1038/s41392-025-02304-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02304-w","url":null,"abstract":"<p>Metabolic reprogramming not only reshapes cellular bioenergetics but also profoundly influences RNA metabolism through metabolite signaling and the RNA-binding activities of metabolic enzymes. Emerging evidence highlights that certain metabolic enzymes act as RNA-binding proteins (RBPs) to regulate gene expression and promote tumor progression. However, the non-catalytic post-transcriptional regulatory functions of metabolic enzymes in hepatocellular carcinoma (HCC) remain largely unexplored. In this study, we performed RNA-protein interactome profiling to identify potential non-canonical RBPs in HCC cells and established phosphoglycerate dehydrogenase (PHGDH) as a functional RBP. We further uncovered a previously unrecognized RNA-binding domain in PHGDH that directly binds cellular mRNAs and plays a key role in HCC cell proliferation. Mechanistically, PHGDH bound directly to the 3’untranslated region (3’UTR) of <i>protein kinase C delta</i> <i>type</i> (<i>PRKCD</i>) mRNA via its RNA-binding domain, thereby stabilizing the transcript and elevating PRKCD protein levels. PHGDH-dependent PRKCD upregulation promoted HCC progression by inducing mitophagy and inhibiting apoptosis. Additionally, decoy oligonucleotides that specifically block the RNA-binding activity of PHGDH markedly impaired its regulation of target genes and suppress HCC cell proliferation. Combination therapy using decoy oligonucleotides or the PRKCD inhibitor sotrastaurin with sorafenib synergistically inhibited HCC progression. Collectively, our findings reveal a non-canonical role of PHGDH in regulating mRNA metabolism and modulating mitophagy. Targeting the RNA-binding activity of PHGDH with decoy oligonucleotides represents a promising therapeutic strategy for HCC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"677 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652273","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}

{"title":"Comprehensive genomic and transcriptomic analyses reveal prognostic stratification for esophageal squamous cell carcinoma","authors":"Jian Gao, Qiming Wang, Fangqiu Fu, Yue Zhao, Teng Yang, Xiangze Li, Yihua Sun, Hong Hu, Longfei Ma, Longsheng Miao, Xiaoyang Luo, Ting Ye, Yiliang Zhang, Yang Zhang, Ziling Huang, Hang Li, Longlong Shao, Midie Xu, Kuaile Zhao, Shiyue Zhang, Mou Zhang, Jun Wang, Chong Dai, Xiaoxiao Shang, Tingyi An, Yawei Zhang, Jiaqing Xiang, Zhiwei Cao, Bin Li, Haiquan Chen","doi":"10.1038/s41392-025-02306-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02306-8","url":null,"abstract":"<p>Recent large-scale multi-omics studies have characterized the heterogeneity of esophageal squamous cell carcinoma (ESCC), but inconsistent clinical management has hindered the identification of prognostic markers and patient stratification. Here, we conducted genomic and transcriptomic profiling of 203 patients from the ECTOP-2002 study with full clinical information. Mutation in the mucin family, as well as APOBEC signature, were associated with poor prognosis. In contrast, activation of the epithelial-keratinization (EpK) pathway was strongly linked to favorable prognosis and lower post-chemotherapy recurrence rates. Independent validation supported S100A8 + S100A9 complex as a key marker of EpK pathway. Furthermore, we established a prognostic stratification system, FU-ESCC subtyping, which defines three subtypes with distinct molecular and clinical features. The EpK-activated subtype retained characteristics of healthy squamous epithelial cells, showed high expression of the S100A8 + S100A9 complex, and was associated with favorable prognosis. The cancer-associated fibroblast (CAF)-enriched subtype showed elevated FAP and Vimentin expression, abundant CAFs, high proliferative activity, and poor prognosis. The immune-desert subtype was characterized by low immune infiltration, suppressed immune signaling, and similarly poor prognosis. Our study provides a valuable resource and insights to better understand ESCC in the era of precision medicine and targeted therapies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645579","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":"Correction: Clinical investigation on nebulized human umbilical cord MSC-derived extracellular vesicles for pulmonary fibrosis treatment","authors":"Meng Li, Huaping Huang, Xiaofei Wei, Huajuan Li, Jun Li, Bingchen Xie, Yuze Yang, Xingyue Fang, Lei Wang, Xiaona Zhang, Heyu Wang, Mengdi Li, Yuting Lin, Dezhi Wang, Yinyin Wang, Tongbiao Zhao, Jianqiu Sheng, Xinbao Hao, Muyang Yan, Lu Xu, Zhijie Chang","doi":"10.1038/s41392-025-02293-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02293-w","url":null,"abstract":"<p>Correction to: <i>Signal Transduction and Targeted Therapy</i> (2025) <b>10</b>:179; https://doi.org/10.1038/s41392-025-02262-3, published online 04 June 2025</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"46 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144652567","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":"DDX39B K63-linked ubiquitination mediated by TRIM28 promotes NSCLC metastasis by enhancing ECAD lysosomal degradation.","authors":"Hang Yuan,Qin Li,Liang Li,Gang Zhao,Jie Zhang,Tianyu Feng,Yafei Guo,Qiming Kou,Siqi Li,Shan Li,Minghui Zhao,Guanru Wang,Qijing Wang,Jie Qu,Huayang Yu,Hongbai Chen,Lunxu Liu,Kai Li,Ping Lin","doi":"10.1038/s41392-025-02305-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02305-9","url":null,"abstract":"Metastasis is a leading cause of treatment failure and high mortality in non-small cell lung cancer (NSCLC). Recently, we demonstrated that DEAD box helicase 39B (DDX39B) was upregulated and activated metabolic reprogramming in colorectal cancer and hepatocellular carcinoma. However, the function of DDX39B and the therapeutic potential for targeting DDX39B in NSCLC remain unclear. Herein, we discovered that DDX39B was an independent marker for poor survival in NSCLC patients. Strikingly, DDX39B protein, but not its mRNA, was elevated in clinical metastatic brain lesions and metastatic cell models (in vitro EMT-metastatic and in vivo carotid artery injection-induced brain-metastatic cell model). Mechanistically, DDX39B interacted with E3 ubiquitin ligase TRIM28 via Pro322 residue and underwent TRIM28-mediated K63-linked ubiquitination at Lys241, Lys384, and Lys398, leading to DDX39B protein stabilization and upregulation. Subsequently, DDX39B directly bound to ECAD and promoted ECAD lysosomal degradation by recruiting Src and Hakai, which was independent of its RNA helicase activity, followed by activating β-catenin oncogenic signaling and facilitating NSCLC aggressive phenotype. According to structure-based virtual screening, we discovered a clinical antimalarial drug, artesunate, that disrupted the association of DDX39B-TRIM28 complex, resulting in DDX39B degradation and blocking the pro-metastatic effects of DDX39B. Overall, our findings uncover that TRIM28/DDX39B/ECAD axis contributes to NSCLC metastasis and targeting DDX39B degradation by artesunate is an effective and promising therapeutic approach for the treatment of NSCLC.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"52 1","pages":"221"},"PeriodicalIF":39.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640190","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":"Bat organoid platform: revolutionizing zoonotic virus research and pandemic preparedness.","authors":"Young-Ho Park,Sun-Uk Kim,Taeho Kwon","doi":"10.1038/s41392-025-02323-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02323-7","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"8 1","pages":"224"},"PeriodicalIF":39.3,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144640010","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":"Dual-immunotherapy triumphs: redefining deficient mismatch repair or high microsatellite instability metastatic colorectal cancer first-line treatment","authors":"Zhijun Yuan, Saimeng Shi, Shanshan Weng","doi":"10.1038/s41392-025-02322-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02322-8","url":null,"abstract":"<p>In a recent paper published in <i>Lancet</i> by Thierry Andre et al., CheckMate 8HW (NCT04008030) revealed that dual-agent immunotherapy improved the prognosis of deficient mismatch repair or high microsatellite instability (dMMR/MSI-H) metastatic colorectal cancer (mCRC) significantly.¹ The results emphasize the significant therapeutic advantages of combining nivolumab (programmed death-1 inhibitor) and ipilimumab (cytotoxic T-lymphocyte-associated antigen-4 inhibitor) in treating dMMR/MSI-H mCRC, irrespective of comparison with chemotherapy (first-line) or nivolumab monotherapy (all treatment lines).</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"23 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629764","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}