Signal Transduction and Targeted Therapy最新文献

{"title":"Ultra-high dose rate radiotherapy overcomes radioresistance in head and neck squamous cell carcinoma","authors":"Hong-Shuai Li, Ruo Tang, Hua-Shan Shi, Zi-Jian Qin, Xiao-Yang Zhang, Yun-Fei Sun, Zhi-Gong Wei, Chao-Fan Ma, Liu Yang, Ye Chen, Zhe-Ran Liu, Li-Li Zhu, Wen Yang, Li Yang, Ai-Ning Xu, Zhuo Zhang, Shu-Qing Liao, Jin-Shui Shi, Jian-Jun Deng, Xiao-Zhong He, Xing-Chen Peng","doi":"10.1038/s41392-025-02184-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02184-0","url":null,"abstract":"<p>Radiotherapy (RT) resistance in head and neck squamous cell carcinoma (HNSCC) significantly hampers local control and patient prognosis. This study investigated the efficacy and molecular mechanisms of high-energy X-ray-based ultra-high dose rate radiotherapy (UHDR-RT) in overcoming RT resistance. The established RT-resistant HNSCC cell lines and animal models were subjected to UHDR-RT or conventional RT (Conv-RT) via a high-power rhodotron accelerator. Cellular assays assessed the malignant phenotype, viability, and degree of DNA damage, whereas in vivo evaluations focused on tumor proliferation and the tumor immune microenvironment (TiME). Transcriptome sequencing and Olink proteomics were employed to explore the underlying mechanisms involved. In vitro experiments indicated that UHDR-RT suppressed radioresistant cell proliferation and invasion, while promoting apoptosis and exacerbating DNA damage. In contrast, its efficacy in radiosensitive cells was comparable to that of Conv-RT. In vivo studies using patient-derived xenograft nude mice models demonstrated that UHDR-RT only partially reversed RT resistance. Transcriptomic and proteomic analyses of C57BL/6J mice models revealed the predominant role of TiME modulating in reversing radioresistance. Immunofluorescence and flow cytometry confirmed increased CD8⁺ T cells and an increased M1/M2 macrophage ratio post-UHDR-RT. Mechanistically, UHDR-RT activated CD8⁺ T cells, which stimulated M1 macrophages through paracrine IFN-γ signaling, thereby enhancing TiME activation. Furthermore, the activated M1 macrophages secreted CXCL9, which in turn reactivated CD8⁺ T cells, forming a feedforward loop that amplified TiME activation. This study elucidates the dual role of UHDR-RT in directly inducing DNA damage and modulating the TiME, highlighting its potential in treating radioresistant HNSCC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"36 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532795","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":"Engineered mitochondria in diseases: mechanisms, strategies, and applications","authors":"Mingyang Li, Limin Wu, Haibo Si, Yuangang Wu, Yuan Liu, Yi Zeng, Bin Shen","doi":"10.1038/s41392-024-02081-y","DOIUrl":"https://doi.org/10.1038/s41392-024-02081-y","url":null,"abstract":"<p>Mitochondrial diseases represent one of the most prevalent and debilitating categories of hereditary disorders, characterized by significant genetic, biological, and clinical heterogeneity, which has driven the development of the field of engineered mitochondria. With the growing recognition of the pathogenic role of damaged mitochondria in aging, oxidative disorders, inflammatory diseases, and cancer, the application of engineered mitochondria has expanded to those non-hereditary contexts (sometimes referred to as mitochondria-related diseases). Due to their unique non-eukaryotic origins and endosymbiotic relationship, mitochondria are considered highly suitable for gene editing and intercellular transplantation, and remarkable progress has been achieved in two promising therapeutic strategies—mitochondrial gene editing and artificial mitochondrial transfer (collectively referred to as engineered mitochondria in this review) over the past two decades. Here, we provide a comprehensive review of the mechanisms and recent advancements in the development of engineered mitochondria for therapeutic applications, alongside a concise summary of potential clinical implications and supporting evidence from preclinical and clinical studies. Additionally, an emerging and potentially feasible approach involves ex vivo mitochondrial editing, followed by selection and transplantation, which holds the potential to overcome limitations such as reduced in vivo operability and the introduction of allogeneic mitochondrial heterogeneity, thereby broadening the applicability of engineered mitochondria.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"5 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532763","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":"Safety, pharmacokinetics and efficacy of HA121-28 in patients with advanced solid tumors and RET fusion-positive non-small-cell lung cancer: a multicenter, open-label, single-arm phase 1/2 trial","authors":"Dan-Yun Ruan, Wen-Wen Huang, Yongsheng Li, Yanqiu Zhao, Yehui Shi, Yuming Jia, Shundong Cang, Wei Zhang, Jianhua Shi, Jun Chen, Jie Lin, Yunpeng Liu, Jianming Xu, Weiwei Ouyang, Jian Fang, Wu Zhuang, Caigang Liu, Qing Bu, Manxiang Li, Xiangjiao Meng, Meili Sun, Nong Yang, Xiaorong Dong, Yueyin Pan, Xingya Li, Xiujuan Qu, Tongmei Zhang, Xianglin Yuan, Sheng Hu, Wei Guo, Yalun Li, Shengqing Li, Dongying Liu, Feixue Song, Liping Tan, Yan Yu, Xinmin Yu, Aimin Zang, Chang Sun, Qian Zhang, Kai Zou, Mo Dan, Rui-Hua Xu, Hongyun Zhao","doi":"10.1038/s41392-025-02155-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02155-5","url":null,"abstract":"<p>HA121-28, a promising multikinase inhibitor, mainly targets rearranged during transfection (RET) fusions and selectively targets vascular endothelial growth factor receptor-2, endothelial growth factor receptor, and fibroblast growth factor receptor 1-3. The safety, pharmacokinetics, and efficacy of HA121-28 were assessed in advanced solid tumors (phase 1, ClinicalTrials.gov NCT03994484) and advanced RET fusion-positive non-small-cell lung cancer (RET-TKI naive NSCLC, phase 2, ClinicalTrials.gov NCT05117658). HA121-28 was administered orally in doses range from 25 to 800 mg under the 21-day on/7-day off scheme for a 28-day cycle in phase 1 trial. The recommended dose identified in phase 1 (450 mg) was administered for patients during phase 2. The primary endpoints were the maximum tolerated dose (MTD) in phase 1 and the objective response rate (ORR) in phase 2. 162 patients were enrolled in phase 1 and 48 in phase 2. A total of 600 mg once daily was set as MTD. Across 100–800 mg, the exposure of HA121-28 increased in a dose-dependent manner. Consistent between both trials, diarrhea, rash, and prolonged QTc interval, were the most reported treatment-emergent adverse events. 40.0% (phase 1) and 62.5% (phase 2) patients experienced grade ≥3 treatment-related adverse events, respectively. The overall ORR was 26.8% and the median progression-free survival (PFS) was 5.5 months among 97 NSCLC patients with advanced RET fusion receiving a dose at ≥450 mg once daily. HA121-28 showed encouraging efficacy in advanced RET fusion NSCLC and its toxicity was tolerable in most patients. Nevertheless, cardiotoxicity is a notable concern that warrants careful attention.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"23 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517863","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":"A recombinant protein vaccine induces protective immunity against SARS-CoV-2 JN.1 and XBB-lineage subvariants","authors":"Jingyun Yang, Weiqi Hong, Huashan Shi, Zhenling Wang, Cai He, Hong Lei, Hong Yan, Aqu Alu, Danyi Ao, Zimin Chen, Yanan Zhou, Hao Yang, Yun Yang, Wenhai Yu, Cong Tang, Junbin Wang, Bai Li, Qing Huang, Hongbo Hu, Wei Cheng, Haohao Dong, Jian Lei, Lu Chen, Xikun Zhou, Li Yang, Wei Wang, Guobo Shen, Jinliang Yang, Zhiwei Zhao, Xiangrong Song, Qiangming Sun, Youchun Wang, Shuaiyao Lu, Jiong Li, Guangwen Lu, Weimin Li, Yuquan Wei, Xiawei Wei","doi":"10.1038/s41392-025-02154-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02154-6","url":null,"abstract":"<p>The emergence of XBB- and JN.1-lineages with remarkable immune evasion characteristics have led to rises in breakthrough infections within populations. In addition, the unfavorable impacts of immune imprinting, stemming from continuous exposure to antigens from circulated viruses, have been observed to incline immune response against earlier lineages, thereby declining the neutralization to newly emerged Omicron subvariants. In response to this, the advancement of next-generation vaccines against COVID-19 targeting components from new subvariants such as XBB-lineage is imperative. In the current study, a self-assembled trimeric recombinant protein (RBD_XBB.1.5-HR) was generated by concatenating the sequences of the receptor binding domain (RBD) derived from XBB.1.5 with heptad-repeat 1 (HR1) and HR2 sequences from the spike S2 subunit. Adjuvanted-RBD_XBB.1.5-HR induced robust humoral and cellular immune responses, characterized by elevated neutralization against JN.1-inculuded subvariants and a substantial population of antigen-specific T memory cells. Protective immunity conferred by RBD_XBB.1.5-HR vaccine was preserved post-immunization, as evidenced by germinal center B (GC B) and T follicular helper (Tfh) responses, sustained neutralization potency, and an increase in memory B cells (MBCs) and long-lived plasma cells (LLPCs). The RBD_XBB.1.5-HR vaccine showed a favorable boosting effect when administered heterologously after three doses of inactivated virus (IV) and mRNA vaccines. Significantly, it provided protection against live Omicron EG.5.1 viruses in vivo. The monovalent RBD_XBB.1.5-HR vaccine showed favorable safety and immunogenicity, boosting neutralizing antibodies against JN.1- and XBB-lineage subvariants in individuals with prior COVID-19 vaccinations. These findings highlight its clinical potential in safeguarding against circulating Omicron subvariants.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"51 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143495307","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":"Invasion and metastasis in cancer: molecular insights and therapeutic targets","authors":"Yongxing Li, Fengshuo Liu, Qingjin Cai, Lijun Deng, Qin Ouyang, Xiang H.-F. Zhang, Ji Zheng","doi":"10.1038/s41392-025-02148-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02148-4","url":null,"abstract":"<p>The progression of malignant tumors leads to the development of secondary tumors in various organs, including bones, the brain, liver, and lungs. This metastatic process severely impacts the prognosis of patients, significantly affecting their quality of life and survival rates. Research efforts have consistently focused on the intricate mechanisms underlying this process and the corresponding clinical management strategies. Consequently, a comprehensive understanding of the biological foundations of tumor metastasis, identification of pivotal signaling pathways, and systematic evaluation of existing and emerging therapeutic strategies are paramount to enhancing the overall diagnostic and treatment capabilities for metastatic tumors. However, current research is primarily focused on metastasis within specific cancer types, leaving significant gaps in our understanding of the complex metastatic cascade, organ-specific tropism mechanisms, and the development of targeted treatments. In this study, we examine the sequential processes of tumor metastasis, elucidate the underlying mechanisms driving organ-tropic metastasis, and systematically analyze therapeutic strategies for metastatic tumors, including those tailored to specific organ involvement. Subsequently, we synthesize the most recent advances in emerging therapeutic technologies for tumor metastasis and analyze the challenges and opportunities encountered in clinical research pertaining to bone metastasis. Our objective is to offer insights that can inform future research and clinical practice in this crucial field.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462420","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":"Precise targeting of transcriptional co-activators YAP/TAZ annihilates chemoresistant brCSCs by alteration of their mitochondrial homeostasis","authors":"Priyanka Dey Talukdar, Kunal Pramanik, Priya Gatti, Pritha Mukherjee, Deepshikha Ghosh, Himansu Roy, Marc Germain, Urmi Chatterji","doi":"10.1038/s41392-025-02133-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02133-x","url":null,"abstract":"<p>Persistence of drug-resistant breast cancer stem cells (brCSCs) after a chemotherapeutic regime correlates with disease recurrence and elevated mortality. Therefore, deciphering mechanisms that dictate their drug-resistant phenotype is imperative for designing targeted and more effective therapeutic strategies. The transcription factor SOX2 has been recognized as a protagonist in brCSC maintenance, and previous studies have confirmed that inhibition of SOX2 purportedly eliminated these brCSCs. However, pharmacological targeting of transcription factors like SOX2 is challenging due to their structural incongruities and intrinsic disorders in their binding interfaces. Therefore, transcriptional co-activators may serve as a feasible alternative for effectively targeting the brCSCs. Incidentally, transcriptional co-activators YAP/TAZ were found to be upregulated in CD44⁺/CD24^-/ALDH⁺ cells isolated from patient breast tumors and CSC-enriched mammospheres. Interestingly, it was observed that YAP/TAZ exhibited direct physical interaction with SOX2 and silencing <i>YAP/TAZ</i> attenuated SOX2 expression in mammospheres, leading to significantly reduced sphere forming efficiency and cell viability. YAP/TAZ additionally manipulated redox homeostasis and regulated mitochondrial dynamics by restraining the expression of the mitochondrial fission marker, DRP1. Furthermore, YAP/TAZ inhibition induced DRP1 expression and impaired OXPHOS, consequently inducing apoptosis in mammospheres. In order to enhance clinical relevance of the study, an FDA-approved drug verteporfin (VP), was used for pharmacological inhibition of YAP/TAZ. Surprisingly, VP administration was found to reduce tumor-initiating capacity of the mammospheres, concomitant with disrupted mitochondrial homeostasis and significantly reduced brCSC population. Therefore, VP holds immense potential for repurposing and decisively eliminating the chemoresistant brCSCs, offering a potent strategy for managing tumor recurrence effectively.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"81 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462470","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":"A first-in-class selective inhibitor of ERK1/2 and ERK5 overcomes drug resistance with a single-molecule strategy","authors":"Huan Xiao, Aoxue Wang, Wen Shuai, Yuping Qian, Chengyong Wu, Xin Wang, Panpan Yang, Qian Sun, Guan Wang, Liang Ouyang, Qiu Sun","doi":"10.1038/s41392-025-02169-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02169-z","url":null,"abstract":"<p>Despite significant advancements in kinase-targeted therapy, the emergence of acquired drug resistance to targets such as KRAS and MEK remains a challenge. Extracellular-regulated kinase 1/2 (ERK1/2), positioned at the terminus of this pathway, is highly conserved and less susceptible to mutations, thereby garnering attention as a crucial therapeutical target. However, attempts to use monotherapies that target ERK1/2 have achieved only limited clinical success, mainly due to the issues of limited efficacy and the emergence of drug resistance. Herein, we present a proof of concept that extracellular-regulated kinase 5 (ERK5) acts as a compensatory pathway after ERK1/2 inhibition in triple-negative breast cancer (TNBC). By utilizing the principle of polypharmacology, we computationally designed <b>SKLB-D18</b>, a first-in-class molecule that selectively targets ERK1/2 and ERK5, with nanomolar potency and high specificity for both targets. <b>SKLB-D18</b> demonstrated excellent tolerability in mice and demonstrated superior in vivo anti-tumor efficacy, not only exceeding the existing clinical ERK1/2 inhibitor BVD-523, but also the combination regimen of BVD-523 and the ERK5 inhibitor XMD8-92. Mechanistically, we showed that <b>SKLB-D18</b>, as an autophagy agonist, played a role in mammalian target of rapamycin (mTOR)/70 ribosomal protein S6 kinase (p70S6K) and nuclear receptor coactivator 4 (NCOA4)-mediated ferroptosis, which may mitigate multidrug resistance.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143451534","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":"Population-level analyses identify host and environmental variables influencing the vaginal microbiome","authors":"Lang Qin, Tianyong Sun, Xiao Li, Shigang Zhao, Zheng Liu, Changlong Zhang, Congcong Jin, Yanqi Xu, Xuan Gao, Yongzhi Cao, Jiaojiao Wang, Ting Han, Lei Yan, Jialun Song, Fangfang Zhang, Feifei Liu, Yousheng Zhang, Yuzhen Huang, Yuping Song, Yanjun Liu, Jing Zhang, Xiuqing Zhang, Zhina Yao, Honglei Chen, Zhenzhen Zhang, Shengrui Zhao, Yuhan Feng, Ya-nan Zhang, Qian Yu, Fang Cao, Lijuan Zhao, Lei Xie, Ling Geng, Qiang Feng, Han Zhao, Zi-Jiang Chen","doi":"10.1038/s41392-025-02152-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02152-8","url":null,"abstract":"<p>The vaginal microbiome is critical for the reproductive health of women, yet the differential impacts exerted by the host and by ambient environmental variables on the vaginal microbiome remain largely unknown. Here, we conducted a comprehensive cross-sectional study of the relationships between the vaginal microbiome and 81 matched host and environmental variables across 6755 Chinese women. By 16S rRNA sequencing, we identified four core vaginal microbiota with a prevalence of over 90% and a total median abundance of 98.8%. Twenty-four variables, including physiology, lifestyle behaviors, gynecologic history, social and environmental information, were found associated with the microbiome composition, of which bacterial vaginosis (BV) showed the largest effect size. Age was among the strongest explanatory variables and the vaginal microbiome dynamically succeeded with increasing age, especially with a composition turning point at the age of 45. Our mediation analyses indicated that the effects of age on the microbiome could be mediated by variables such as parity number and lifestyles. We further classified the vaginal microbiomes of the population into 13 “Vagitypes”. Women with <i>Lactobacillus iners</i>- and <i>Lactobacillus jensenii</i>-dominated Vagitypes had significantly higher live birth rate than those with Vagitype dominated by <i>Fannyhessea vaginae</i> (53.40%, 59.09% vs 21.43%; OR [95% CI]: 3.62 [1.12–14.87], 5.39 [1.27–27.36]; <i>P</i> = 0.031, <i>P</i> = 0.021). This study provides a comprehensive overview of the associations between identified variables and the vaginal microbiome, representing an important step toward understanding of environment-microbe-host interactions.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"24 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443417","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":"Breast cancer: pathogenesis and treatments","authors":"Xin Xiong, Le-Wei Zheng, Yu Ding, Yu-Fei Chen, Yu-Wen Cai, Lei-Ping Wang, Liang Huang, Cui-Cui Liu, Zhi-Ming Shao, Ke-Da Yu","doi":"10.1038/s41392-024-02108-4","DOIUrl":"https://doi.org/10.1038/s41392-024-02108-4","url":null,"abstract":"<p>Breast cancer, characterized by unique epidemiological patterns and significant heterogeneity, remains one of the leading causes of malignancy-related deaths in women. The increasingly nuanced molecular subtypes of breast cancer have enhanced the comprehension and precision treatment of this disease. The mechanisms of tumorigenesis and progression of breast cancer have been central to scientific research, with investigations spanning various perspectives such as tumor stemness, intra-tumoral microbiota, and circadian rhythms. Technological advancements, particularly those integrated with artificial intelligence, have significantly improved the accuracy of breast cancer detection and diagnosis. The emergence of novel therapeutic concepts and drugs represents a paradigm shift towards personalized medicine. Evidence suggests that optimal diagnosis and treatment models tailored to individual patient risk and expected subtypes are crucial, supporting the era of precision oncology for breast cancer. Despite the rapid advancements in oncology and the increasing emphasis on the clinical precision treatment of breast cancer, a comprehensive update and summary of the panoramic knowledge related to this disease are needed. In this review, we provide a thorough overview of the global status of breast cancer, including its epidemiology, risk factors, pathophysiology, and molecular subtyping. Additionally, we elaborate on the latest research into mechanisms contributing to breast cancer progression, emerging treatment strategies, and long-term patient management. This review offers valuable insights into the latest advancements in Breast Cancer Research, thereby facilitating future progress in both basic research and clinical application.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143443418","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":"Induction chemotherapy followed by camrelizumab plus apatinib and chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: a multicenter, single-arm trial","authors":"Ming Liu, Guihuan Qiu, Wenhui Guan, Xiaohong Xie, Xinqing Lin, Zhanhong Xie, Jiexia Zhang, Yinyin Qin, Haijian Du, Xin Chen, Yu Deng, Shiyue Li, Nanshan Zhong, Chengzhi Zhou","doi":"10.1038/s41392-025-02153-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02153-7","url":null,"abstract":"<p>Chemo-immunotherapy is the current first-line treatment for patients with extensive-stage small cell lung cancer (ES-SCLC), but survival benefits are modest. We aimed to evaluate the safety, antitumor activity and biomarkers of first-line camrelizumab and apatinib plus chemotherapy in untreated ES-SCLC patients. In this single-arm trial (ClinicalTrials.gov NCT05001412), eligible patients received 2 cycles of etoposide and carboplatin (EC) as induction treatment followed by 2–4 cycles of camrelizumab, apatinib plus EC, then maintenance camrelizumab plus apatinib. Primary endpoint was safety. Secondary endpoints included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Targeted sequencing and whole transcriptome sequencing were performed to explore biomarkers. All enrolled 40 patients were treated and analyzed for safety. During the entire treatment, treatment-emergent adverse events (TEAEs) occurred in 40 patients (100%), and 30 (75.0%) were grade ≥3. The most common grade ≥3 TEAEs were neutropenia (35.0%), anemia (15.0%) and increased alanine aminotransferase (15.0%). No treatment-related deaths occurred. Among 36 evaluable patients, ORR was 88.9% (95% CI: 73.9%–96.9%), median PFS was 7.3 months (95% CI: 6.6–9.2) and median OS was 17.3 months (11.8-not reached). Mutations in RB1, high levels of tumor mutation burden, natural killer cells, and interferons, and low levels of cancer-associated fibroblasts, correlated with prolonged PFS. Induction chemotherapy followed by camrelizumab, apatinib plus EC demonstrated acceptable safety and promising antitumor activity in untreated ES-SCLC patients. The identified biomarkers need further validation.</p><p><b>Trial Registration</b> ClinicalTrials.gov Identifier: NCT05001412.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"24 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435282","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}