Signal Transduction and Targeted Therapy最新文献

{"title":"CHIKV mRNA vaccines encoding conserved structural/envelope proteins confer broad cross-lineage protection against infection","authors":"Xiaoming Liang, Yanan Zhou, Yun Yang, Qianqian Li, Junbin Wang, Bai Li, Hao Yang, Cong Tang, Wenhai Yu, Haixuan Wang, Qing Huang, Hongyu Chen, Yuhuan Yan, Ran An, Dongdong Lin, Wenqi Quan, Yong Zhang, Yanwen Li, Xuena Du, Yuxia Yuan, Longhai Yuan, Jian Zhou, Qiangming Sun, Youchun Wang, Shuaiyao Lu","doi":"10.1038/s41392-025-02182-2","DOIUrl":"https://doi.org/10.1038/s41392-025-02182-2","url":null,"abstract":"<p>With the broad spread of the chikungunya virus (CHIKV), there is an increasing demand for more effective and broadly protective vaccines. Here, we designed CHIKV mRNA vaccines containing full-length structural proteins or part of structural proteins (envelope proteins) based on conserved sequences from 769 viral strains encompassing four lineages. The vaccine induced strong cellular and humoral immune responses in BALB/c mice and provided robust protection. Immunization of BALB/c mice with either of the two vaccines induced high levels of neutralizing antibodies against pseudoviruses from four distinct lineages, highlighting their potential for broad cross-lineage protective efficacy. Immunoglobulin repertoire analysis revealed two important BCR V-J gene combinations, IgHV1-4-IgHJ3 and IgHV1-4-IgHJ2, and lineage-specific immunity analysis revealed significant upregulation of TCRs containing V19 and V20. BCR and TCR immunodiversity may be a potential reason for the broad-spectrum protection against CHIKV afforded by the vaccine. In A129 mice, it elicited lower levels of neutralizing antibodies but prevented mouse mortality and cleared chronic infection. In the rhesus macaque model, both vaccines elicited a certain level of humoral and cellular immune responses and protected the rhesus macaques from the CHIKV challenge. In conclusion, the results from both mouse and rhesus macaque models indicate that the vaccine could be a candidate for clinical use against CHIKV.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143723179","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 classification of hormone receptor-positive /HER2-positive breast cancer reveals potential neoadjuvant therapeutic strategies","authors":"Chao Liu, Lisha Sun, Nan Niu, Pengjie Hou, Guanglei Chen, Hao Wang, Zhan Zhang, Xiaofan Jiang, Qianshi Xu, Yafei Zhao, Yimin Wang, Yuan Shi, Mingxin Liu, Yongliang Yang, Wei Qian, Jiandong Wang, Caigang Liu","doi":"10.1038/s41392-025-02181-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02181-3","url":null,"abstract":"<p>Significant heterogeneity exists in hormone receptor (HR)-positive/HER2-positive (HR⁺/HER2⁺) breast cancer, contributing to suboptimal pathological complete response rates with conventional neoadjuvant treatment regimens. Overcoming this challenge requires precise molecular classification, which is pivotal for the development of targeted therapies. We conducted molecular typing on a cohort of 211 patients with HR⁺/HER2⁺ breast cancer and performed a comprehensive analysis of the efficacy of various neoadjuvant treatment regimens. Our findings revealed four distinct molecular subtypes, each exhibiting unique characteristics and therapeutic implications. The HER2-enriched subtype, marked by activation of the HER2 signaling and hypoxia-inducible factor 1 (HIF-1) pathway, may benefit from intensified anti-HER2-targeted therapy. Estrogen receptor (ER)-activated subtype demonstrated potential sensitivity to combined therapeutic strategies targeting both ER and HER2 pathways. Characterized by high immune cell infiltration, the immunomodulatory subtype showed sensitivity to HER2-targeted antibody–drug conjugates (ADCs) and promise for immune checkpoint therapy. The highly heterogeneous subtype requires a multifaceted therapeutic approach. Organoid susceptibility assays suggested phosphoinositide 3-kinase inhibitors may be a potential treatment option. These findings underscore the importance of molecular subtyping in HR⁺/HER2⁺ breast cancer, offering a framework for developing precise and personalized treatment strategies. By addressing the heterogeneity of the disease, these approaches have the potential to optimize therapeutic outcomes and improve patient care.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"29 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143702976","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":"Intranasal prime-boost RNA vaccination elicits potent T cell response for lung cancer therapy","authors":"Hongjian Li, Yating Hu, Jingxuan Li, Jia He, Guocan Yu, Jiasheng Wang, Xin Lin","doi":"10.1038/s41392-025-02191-1","DOIUrl":"https://doi.org/10.1038/s41392-025-02191-1","url":null,"abstract":"<p>The rapid success of RNA vaccines in preventing SARS-CoV-2 has sparked interest in their use for cancer immunotherapy. Although many cancers originate in mucosal tissues, current RNA cancer vaccines are mainly administered non-mucosally. Here, we developed a non-invasive intranasal cancer vaccine utilizing circular RNA encapsulated in lipid nanoparticles to induce localized mucosal immune responses. This strategy elicited potent anti-tumor T cell responses in preclinical lung cancer models while mitigating the systemic adverse effects commonly associated with intravenous RNA vaccination. Specifically, type 1 conventional dendritic cells were indispensable for T cell priming post-vaccination, with both alveolar macrophages and type 1 conventional dendritic cells boosting antigen-specific T cell responses in lung tissues. Moreover, the vaccination facilitated the expansion of both endogenous and adoptive transferred antigen-specific T cells, resulting in robust anti-tumor efficacy. Single-cell RNA sequencing revealed that the vaccination reprograms endogenous T cells, enhancing their cytotoxicity and inducing a memory-like phenotype. Additionally, the intranasal vaccine can modulate the response of CAR-T cells to augment therapeutic efficacy against tumor cells expressing specific tumor-associated antigens. Collectively, the intranasal RNA vaccine strategy represents a novel and promising approach for developing RNA vaccines targeting mucosal malignancies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"183 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677759","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":"Fibroblastic niches in action: CCL19+ reticular cells drive anti-tumor immunity in lung cancer","authors":"Alessandro Ianni, Alejandro Vaquero, Thomas Braun","doi":"10.1038/s41392-025-02185-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02185-z","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"28 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143677704","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":"An unexpected player in organ tropism: aspartate functions as signalling molecule to drive lung metastasis","authors":"Felix C. E. Vogel, Almut Schulze","doi":"10.1038/s41392-025-02189-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02189-9","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665854","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 PI3K inhibitor resistance in breast cancer with metabolic drugs","authors":"Niklas Gremke, Isabelle Besong, Alina Stroh, Luise von Wichert, Marie Witt, Sabrina Elmshäuser, Michael Wanzel, Martin F. Fromm, R. Verena Taudte, Sabine Schmatloch, Thomas Karn, Mattea Reinisch, Nader Hirmas, Sibylle Loibl, Thomas Wündisch, Anne-Sophie Litmeyer, Paul Jank, Carsten Denkert, Sebastian Griewing, Uwe Wagner, Thorsten Stiewe","doi":"10.1038/s41392-025-02180-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02180-4","url":null,"abstract":"<p>Activating <i>PIK3CA</i> mutations, present in up to 40% of hormone receptor-positive (HR⁺), human epidermal growth factor receptor 2-negative (Her2⁻) breast cancer (BC) patients, can be effectively targeted with the alpha isoform-specific PI3K inhibitor Alpelisib. This treatment significantly improves outcomes for HR⁺, Her2⁻, and <i>PIK3CA</i>-mutated metastatic BC patients. However, acquired resistance, often due to aberrant activation of the mTOR complex 1 (mTORC1) pathway, remains a significant clinical challenge. Our study, using in vitro and orthotopic xenograft mouse models, demonstrates that constitutively active mTORC1 signaling renders PI3K inhibitor-resistant BC exquisitely sensitive to various drugs targeting cancer metabolism. Mechanistically, mTORC1 suppresses the induction of autophagy during metabolic perturbation, leading to energy stress, a critical depletion of aspartate, and ultimately cell death. Supporting this mechanism, BC cells with CRISPR/Cas9-engineered knockouts of canonical autophagy genes showed similar vulnerability to metabolically active drugs. In BC patients, high mTORC1 activity, indicated by 4E-BP1^T37/46 phosphorylation, correlated with p62 accumulation, a sign of impaired autophagy. Together, these markers predicted poor overall survival in multiple BC subgroups. Our findings reveal that aberrant mTORC1 signaling, a common cause of PI3K inhibitor resistance in BC, creates a druggable metabolic vulnerability by suppressing autophagy. Additionally, the combination of 4E-BP1^T37/46 phosphorylation and p62 accumulation serves as a biomarker for poor overall survival, suggesting their potential utility in identifying BC patients who may benefit from metabolic therapies.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"37 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665855","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 BCL2 family: from apoptosis mechanisms to new advances in targeted therapy","authors":"Meike Vogler, Yannick Braun, Victoria M. Smith, Mike-Andrew Westhoff, Raquel S. Pereira, Nadja M. Pieper, Marius Anders, Manon Callens, Tim Vervliet, Maha Abbas, Salvador Macip, Ralf Schmid, Geert Bultynck, Martin JS Dyer","doi":"10.1038/s41392-025-02176-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02176-0","url":null,"abstract":"<p>The B cell lymphoma 2 (BCL2) protein family critically controls apoptosis by regulating the release of cytochrome c from mitochondria. In this cutting-edge review, we summarize the basic biology regulating the BCL2 family including canonical and non-canonical functions, and highlight milestones from basic research to clinical applications in cancer and other pathophysiological conditions. We review laboratory and clinical development of BH3-mimetics as well as more recent approaches including proteolysis targeting chimeras (PROTACs), antibody-drug conjugates (ADCs) and tools targeting the BH4 domain of BCL2. The first BCL2-selective BH3-mimetic, venetoclax, showed remarkable efficacy with manageable toxicities and has transformed the treatment of several hematologic malignancies. Following its success, several chemically similar BCL2 inhibitors such as sonrotoclax and lisaftoclax are currently under clinical evaluation, alone and in combination. Genetic analysis highlights the importance of BCL-X_L and MCL1 across different cancer types and the possible utility of BH3-mimetics targeting these proteins. However, the development of BH3-mimetics targeting BCL-X_L or MCL1 has been more challenging, with on-target toxicities including thrombocytopenia for BCL-X_L and cardiac toxicities for MCL1 inhibitors precluding clinical development. Tumor-specific BCL-X_L or MCL1 inhibition may be achieved by novel targeting approaches using PROTACs or selective drug delivery strategies and would be transformational in many subtypes of malignancy. Taken together, we envision that the targeting of BCL2 proteins, while already a success story of translational research, may in the foreseeable future have broader clinical applicability and improve the treatment of multiple diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"7 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143665856","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":"Massively parallel interrogation of human functional variants modulating cancer immunosurveillance","authors":"Ying Liu, Yongshuo Liu, Xuran Niu, Ang Chen, Yizhou Li, Ying Yu, Binrui Mo, Zhiheng Liu, Tao Xu, Jie Cheng, Zeguang Wu, Wensheng Wei","doi":"10.1038/s41392-025-02171-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02171-5","url":null,"abstract":"<p>Anti-PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized clinical cancer treatment, while abnormal PD-L1 or HLA-I expression in patients can significantly impact the therapeutic efficacy. Somatic mutations in cancer cells that modulate these critical regulators are closely associated with tumor progression and ICB response. However, a systematic interpretation of cancer immune-related mutations is still lacking. Here, we harnessed the ABEmax system to establish a large-scale sgRNA library encompassing approximately 820,000 sgRNAs that target all feasible serine/threonine/tyrosine residues across the human genome, which systematically unveiled thousands of novel mutations that decrease or augment PD-L1 or HLA-I expression. Beyond residues associated with phosphorylation events, our screens also identified functional mutations that affect mRNA or protein stability, DNA binding capacity, protein-protein interactions, and enzymatic catalytic activity, leading to either gene inactivation or activation. Notably, we uncovered certain mutations that concurrently modulate PD-L1 and HLA-I expression, represented by the clinically relevant mutation SETD2_Y1666. We demonstrated that this mutation induces consistent phenotypic effects across multiple cancer cell lines and enhances the efficacy of immunotherapy in different tumor models. Our findings provide an unprecedented resource of functional residues that regulate cancer immunosurveillance, offering valuable guidance for clinical diagnosis, ICB therapy, and the development of innovative drugs for cancer treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653368","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":"Photodynamic gel-bombs enhance tumor penetration and downstream synergistic therapies","authors":"Xiaole Bai, Fanliang Meng, Xuejiao Wang, Linyun He, Chao Fan, Liangjie Tian, Yangning Zhang, Jiahao Pan, Qun Wu, Xiangrong Hao, Ying Wang, Bo-Feng Zhu, Jun-Bing Fan, Bin Cong","doi":"10.1038/s41392-025-02186-y","DOIUrl":"https://doi.org/10.1038/s41392-025-02186-y","url":null,"abstract":"<p>Nanoparticle-based drug delivery system remains a significant challenge in the current treatment of solid tumors, primarily due to their limited penetration capabilities. Herein, we successfully engineer photodynamic gel-bombs (DCM@OPR) capable of penetrating deeply into tumor tissues utilizing the photodynamic-triggered explosive energy and receptor-mediated transcytosis, significantly enhancing the therapeutic efficacy of breast cancer. The photodynamic gel-bombs were fabricated by loading powerful components of chlorin e6 and MnO₂ nanoparticles, as well as Doxorubicin, into a crosslinked Ca²⁺-gel. Upon exposure to laser irradiation, the obtained photodynamic gel-bombs are capable of generating explosive energy, resulting in their fragmentation into numerous nanofragments. The photodynamic-triggered explosive energy subsequently drives these nanofragments to deeply penetrate into tumor tissues through gap leakage among tumor cells. In addition, the photodynamic-triggered explosive energy also promotes the escape of those therapeutic components (including chlorin e6, MnO₂ nanoparticles, and doxorubicin) and nanofragments from lysosomes. In the subsequent stages, these nanofragments also exhibit excellent transcytosis capacity, facilitating deep penetration into tumor tissues. As expected, the enhanced penetration and accumulation of therapeutic components into tumor tissues can be achieved, significantly enhancing the anti-proliferation capacity against breast cancer.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653386","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 KN026, a bispecific anti-HER2 antibody, in combination with KN046, an anti-CTLA4/PD-L1 antibody, in patients with advanced HER2-positive nonbreast cancer: a combined analysis of a phase Ib and a phase II study","authors":"Dan Liu, Jifang Gong, Jian Li, Changsong Qi, Zuoxing Niu, Bo Liu, Zhi Peng, Suxia Luo, Xicheng Wang, Yakun Wang, Rusen Zhao, Lilin Chen, Ting Deng, Zhen Li, Lei Chen, Meimei Fang, Hongwei Yang, Linzhi Lu, Yanming Zhang, Fengling Kang, Ting Xu, Xiaotian Zhang, Lin Shen","doi":"10.1038/s41392-025-02195-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02195-x","url":null,"abstract":"<p>To evaluate the efficacy and safety of KN026, a novel bispecific HER2 (ECD2 and ECD4) antibody, plus KN046, a PD-L1, and CTLA4 bispecific antibody, in patients with advanced HER2-positive solid tumors. We conducted two sequentially designed phase Ib and II studies with similar target populations and evaluation schedules. The primary endpoints included safety, maximum tolerated dose (MTD), the recommended phase II dose (RP2D) for the phase Ib study, and the objective response rate (ORR) and duration of response (DoR) for the phase II study. Hereby, we solely report the results from 113 nonbreast cancer patients. In phase Ib, MTD was not reached. Dose 3 was confirmed to be acceptable for the phase II study. An objective response has been exclusively observed in HER2-positive patients. Any grade treatment-related adverse events (TRAEs) were reported in 108 (95.6%) patients. The most common TRAEs were infusion reactions (38.9%), anemia (37.2%), elevated AST (31.0%), and diarrhea (30.1%). Among the 108 patients evaluated for efficacy, the overall ORR was 55.6% (95%CI, 45.7%, 65.1%). In the HER2-positive GC subgroup, 38 patients received this regimen as the 1st-line treatment and 30 patients achieved an objective response, with an ORR of 78.9% (95%CI, 62.7%, 90.4%). Among 27 pretreated patients, the ORR was 44.4% (95%CI, 25.5%, 64.7%). In the other HER2-positive solid tumor subgroup (n = 34), the ORR was 52.9% (95%CI 35.1%,70.2%). Thus, KN026 plus KN04 exhibits promising efficacy and acceptable safety profiles in HER2-positive nonbreast cancer, as does the 1st-line treatment for GC.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653383","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}