Signal Transduction and Targeted Therapy最新文献

{"title":"Myeloid but not hepatocytic CD38 is a key driver for hepatic ischemia/reperfusion injury.","authors":"Qi-Hang Zhao,Ya-Ting Zhang,Ke Wen,Qi Ding,Zi-Ying Chen,Dilinuer Tula,Jia-Hui Li,Juan Zhou,Yun-Fei Xiao,Xiao-Hui Guan,Ke-Yu Deng,Ling-Fang Wang,Hong-Bo Xin","doi":"10.1038/s41392-025-02233-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02233-8","url":null,"abstract":"Hepatic ischemia-reperfusion injury (HIRI) is a critical condition that often occurs during liver transplantation and surgical liver resection. However, its mechanism has not been fully elucidated. Nicotinamide adenine dinucleotide (NAD+), functioning as a coenzyme or cofactor, is crucial for both redox and non-redox processes. In mammals, CD38 serves as the primary enzyme responsible for NAD+ degradation. In this study, we reported that the absence of CD38 markedly reduces HIRI in CD38 global knockout (CD38KO) and CD38 myeloid-specific knockout (CD38MKO) mice, but not in CD38 hepatocyte-specific knockout (CD38LKO) mice compared with the control (CD38fl/fl) mice by suppressing HIRI-induced hepatic oxidative stress, inflammatory responses, and pyroptosis. The findings were corroborated by a noticeable decrease in levels of alanine aminotransferase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH), along with reduced necrosis. Besides, we found that the expressions of SIRT1 and its downstream targets, p53 and PPARγ, were elevated in the liver tissues of CD38KO and CD38MKO mice compared to CD38fl/fl mice, while the acetylation levels of p53 were reduced. Furthermore, we demonstrated that myeloid CD38 deficiency not only promoted M2-type polarization and inhibited M1-type polarization of macrophages but also suppressed NLRP3-mediated pyroptosis by triggering NAD+/SIRT1 signaling in macrophages, resulting in the reduction of oxidative stress, inflammation, and pyroptosis in the liver, ultimately protecting against HIRI. This study highlights myeloid CD38 as a promising target for the prevention and treatment of HIRI clinically.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":"150"},"PeriodicalIF":39.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926384","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":"Viral blips and hidden infections: pitfalls in HIV-1 prophylaxis by broadly neutralizing antibodies.","authors":"Fabian Zech,Frank Kirchhoff","doi":"10.1038/s41392-025-02230-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02230-x","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"44 1","pages":"156"},"PeriodicalIF":39.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926385","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 molecular mechanism and therapeutic landscape of copper and cuproptosis in cancer.","authors":"Ziyu Guo,Danyao Chen,Lei Yao,Yuming Sun,Daishi Li,Jiayuan Le,Yating Dian,Furong Zeng,Xiang Chen,Guangtong Deng","doi":"10.1038/s41392-025-02192-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02192-0","url":null,"abstract":"Copper, an essential micronutrient, plays significant roles in numerous biological functions. Recent studies have identified imbalances in copper homeostasis across various cancers, along with the emergence of cuproptosis, a novel copper-dependent form of cell death that is crucial for tumor suppression and therapeutic resistance. As a result, manipulating copper levels has garnered increasing interest as an innovative approach to cancer therapy. In this review, we first delineate copper homeostasis at both cellular and systemic levels, clarifying copper's protumorigenic and antitumorigenic functions in cancer. We then outline the key milestones and molecular mechanisms of cuproptosis, including both mitochondria-dependent and independent pathways. Next, we explore the roles of cuproptosis in cancer biology, as well as the interactions mediated by cuproptosis between cancer cells and the immune system. We also summarize emerging therapeutic opportunities targeting copper and discuss the clinical associations of cuproptosis-related genes. Finally, we examine potential biomarkers for cuproptosis and put forward the existing challenges and future prospects for leveraging cuproptosis in cancer therapy. Overall, this review enhances our understanding of the molecular mechanisms and therapeutic landscape of copper and cuproptosis in cancer, highlighting the potential of copper- or cuproptosis-based therapies for cancer treatment.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"26 1","pages":"149"},"PeriodicalIF":39.3,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926323","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":"First-line treatment of anti-EGFR monoclonal antibody cetuximab β plus FOLFIRI versus FOLFIRI alone in Chinese patients with RAS/BRAF wild-type metastatic colorectal cancer: a randomized, phase 3 trial.","authors":"Yuankai Shi,Yi Ba,Junye Wang,Jianping Xiong,Kangsheng Gu,Yigui Chen,Zhendong Zheng,Zishu Wang,Weijian Guo,Ying Cheng,Xianli Yin,Yunpeng Liu,Yuxian Bai,Enxiao Li,Qi Li,Liangjun Zhu,Wei Li,Da Jiang,Jingdong He,Jiansi Chen,Jianguo Sun,Sheng Hou","doi":"10.1038/s41392-025-02229-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02229-4","url":null,"abstract":"Cetuximab plus irinotecan, fluorouracil, and leucovorin (FOLFIRI) represents a first-line therapeutic standard for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients. Despite this established approach, cetuximab β (CMAB009), as a modified antibody of cetuximab, prospectively selected for dual RAS/BRAF wild-type patients, has not yet been validated in the Chinese mCRC patients through phase 3 trial. In this study (ClinicalTrials.gov identifier: NCT03206151), patients with RAS/BRAF wild-type mCRC who were not suitable for radical resection were randomly assigned in a 1:1 ratio to receive cetuximab β plus FOLFIRI or FOLFIRI alone. The primary endpoint was blinded independent review committee-assessed progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), surgery rate for metastasis and R0 resection rate, and safety. From January 4, 2018 to September 2, 2021, a total of 505 eligible patients were enrolled and received study treatment; the median follow-up duration was 8.7 months (95% confidence interval [CI], 7.77 to 9.29) and 5.9 months (95% CI, 5.63 to 6.65) in cetuximab β plus FOLFIRI group and FOLFIRI group, respectively. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI demonstrated statistically significant improvements in median PFS (13.1 vs. 9.6 months, hazard ratio [HR], 0.639; 95% CI, 0.468 to 0.872; P = 0.004), median OS (28.3 vs. 23.1 months, HR, 0.729; 95% CI, 0.551 to 0.965; P = 0.024), and ORR (69.1% vs. 42.3%, odds ratio, 3.090; 95% CI, 2.280 to 4.189; P < 0.001). Cetuximab β plus FOLFIRI exhibited manageable toxicity without novel safety signals. This study demonstrated that cetuximab β plus FOLFIRI provided significant clinical benefits as a first-line treatment for patients with RAS/BRAF wild-type mCRC. Compared to FOLFIRI alone, cetuximab β plus FOLFIRI therapy led to prolonged median PFS and OS while maintaining a manageable safety profile, offering a new treatment option for this patient population.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"25 1","pages":"147"},"PeriodicalIF":39.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915037","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":"Oncogenic proteome of pancreatic cancer extracellular vesicles: sodium/myo-inositol cotransporter as a potential marker.","authors":"Arunima Panda,Krish Ragunath,Marina Pajic,David W Greening,Marco Falasca","doi":"10.1038/s41392-025-02232-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02232-9","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"50 1","pages":"148"},"PeriodicalIF":39.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915035","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":"Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.","authors":"Xiaolei Wu,Zhangzhong Yang,Jinjun Zou,Huile Gao,Zhenhua Shao,Chuanzhou Li,Peng Lei","doi":"10.1038/s41392-025-02179-x","DOIUrl":"https://doi.org/10.1038/s41392-025-02179-x","url":null,"abstract":"Neurodegenerative diseases (e.g., Alzheimer's, Parkinson's, Huntington's disease, and Amyotrophic Lateral Sclerosis) are major health threats for the aging population and their prevalences continue to rise with the increasing of life expectancy. Although progress has been made, there is still a lack of effective cures to date, and an in-depth understanding of the molecular and cellular mechanisms of these neurodegenerative diseases is imperative for drug development. Protein phosphorylation, regulated by protein kinases and protein phosphatases, participates in most cellular events, whereas aberrant phosphorylation manifests as a main cause of diseases. As evidenced by pharmacological and pathological studies, protein kinases are proven to be promising therapeutic targets for various diseases, such as cancers, central nervous system disorders, and cardiovascular diseases. The mechanisms of protein phosphatases in pathophysiology have been extensively reviewed, but a systematic summary of the role of protein kinases in the nervous system is lacking. Here, we focus on the involvement of protein kinases in neurodegenerative diseases, by summarizing the current knowledge on the major kinases and related regulatory signal transduction pathways implicated in diseases. We further discuss the role and complexity of kinase-kinase networks in the pathogenesis of neurodegenerative diseases, illustrate the advances of clinical applications of protein kinase inhibitors or novel kinase-targeted therapeutic strategies (such as antisense oligonucleotides and gene therapy) for effective prevention and early intervention.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"13 1","pages":"146"},"PeriodicalIF":39.3,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915036","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":"Meningeal lymphatic drainage: novel insights into central nervous system disease","authors":"Qiang Zhang, Yin Niu, Yingpei Li, Chenyang Xia, Zhi Chen, Yujie Chen, Hua Feng","doi":"10.1038/s41392-025-02177-z","DOIUrl":"https://doi.org/10.1038/s41392-025-02177-z","url":null,"abstract":"<p>In recent years, increasing evidence has suggested that meningeal lymphatic drainage plays a significant role in central nervous system (CNS) diseases. Studies have indicated that CNS diseases and conditions associated with meningeal lymphatic drainage dysfunction include neurodegenerative diseases, stroke, infections, traumatic brain injury, tumors, functional cranial disorders, and hydrocephalus. However, the understanding of the regulatory and damage mechanisms of meningeal lymphatics under physiological and pathological conditions is currently limited. Given the importance of a profound understanding of the interplay between meningeal lymphatic drainage and CNS diseases, this review covers seven key aspects: the development and structure of meningeal lymphatic vessels, methods for observing meningeal lymphatics, the function of meningeal lymphatics, the molecular mechanisms of meningeal lymphatic injury, the relationships between meningeal lymphatic vessels and CNS diseases, potential regulatory mechanisms of meningeal lymphatics, and conclusions and outstanding questions. We will explore the relationship between the development, structure, and function of meningeal lymphatics, review current methods for observing meningeal lymphatic vessels in both animal models and humans, and identify unresolved key points in meningeal lymphatic research. The aim of this review is to provide new directions for future research and therapeutic strategies targeting meningeal lymphatics by critically analyzing recent advancements in the field, identifying gaps in current knowledge, and proposing innovative approaches to address these gaps.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"98 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909877","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 cancer: tumor-specific splicing events give rise to immunogenic, tumor-wide neoantigens","authors":"Nils Kosiol, Annkristin Heine, Peter Brossart","doi":"10.1038/s41392-025-02237-4","DOIUrl":"https://doi.org/10.1038/s41392-025-02237-4","url":null,"abstract":"<p>In a recent study published in <i>Nature</i>,¹ Kwok et al. identified tumor-wide antigens that derived from tumor-specific splicing events, known as neojunctions (NJs) (Fig. 1a). The study identified two distinct neopeptide-encoding NJs (NEJs) that were spatially and temporally conserved in glioblastoma (GBM) patients and induced an HLA-dependent T cell response. The discovery of these NEJs, as well as the pipeline used for their identification, harbors significant potential for the development of tumor vaccines and adoptive cell therapies that might be effective across various cancer entities.</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-025-02237-4/MediaObjects/41392_2025_2237_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"508\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41392-025-02237-4/MediaObjects/41392_2025_2237_Fig1_HTML.png\" width=\"685\"/></picture><p><b>a</b> Schematic overview of an example for a neojunction. <b>b–g</b> Work process that led to the discovery of public, tumor-wide, NJ-derived immunogenic neoantigens. <b>b</b> shows the 12 tumors that were investigated from the TCGA data sets. GBM glioblastoma, LGG low-grade glioma, MESO mesothelioma, LUAD lung adenocarcinoma, LIHC liver hepatocellular carcinoma, STAD stomach adenocarcinoma, KIRP kidney renal papillary cell carcinoma, LUSC lung squamous cell carcinoma, COAD colon adenocarcinoma, KICH Kidney chromophobe, PRAD Prostate adenocarcinoma, SKCM skin cutaneous melanoma. <b>c</b> Investigation of spatial distribution of public NJs was done by analyzing existing data sets and acquiring 10 spatially separated biopsies from 51 glioma patients. <b>d</b> Temporal conversation was investigated in data sets of recurring tumors and metastases. <b>e</b> NJ expression and HLA presentation were investigated using pre-existing MS data sets and bioinformatical prediction. <b>f</b> NJs that were public, tumor-wide, expressed and temporally conserved were selected for immunogenicity. <b>g</b> Induction of immunity by NEJs was confirmed with APC-based T cell activation and subsequent tumor cell killing by NEJ-targeting T cells. The figure was created with Biorender</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"59 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909875","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":"Overexpressing natural killer group 2 member A drives natural killer cell exhaustion in relapsed acute myeloid leukemia","authors":"Juan Xie, Xue-Fei Liu, Tong Zhou, Long Liu, Rui-Qin Hou, Xing-Xing Yu, Ze-Ying Fan, Qian-Nan Shang, Ying-Jun Chang, Xiao-Su Zhao, Yu Wang, Lan-Ping Xu, Xiao-Hui Zhang, Xiao-Jun Huang, Xiang-Yu Zhao","doi":"10.1038/s41392-025-02228-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02228-5","url":null,"abstract":"<p>Acute myeloid leukemia (AML) relapse is associated with poor prognosis. While natural killer (NK) cell therapy can induce leukemia remission, infused NK cells are prone to exhaustion. Elucidating the molecular mechanisms driving NK cell exhaustion in AML patients could provide critical insights for developing novel strategies to optimize NK cell-based immunotherapies. In this study, we systematically investigated NK cell exhaustion in relapsed AML patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT) through phenotypic assessments, functional assays, and RNA sequencing analyses. Compared to NK cells from complete remission patients and healthy controls, NK cells from relapsed AML patients exhibited an exhausted phenotype, marked by reduced maturity, elevated expression of the inhibitory receptor NKG2A, impaired cytotoxicity, and suppression of the PI3K-AKT pathway. Notably, NKG2A expression levels on NK cells correlated with disease progression. Blockade or genetic knockout of NKG2A effectively reversed NK cell exhaustion both in vitro and in an AML mouse model. Furthermore, activation of the PI3K-AKT pathway significantly enhanced cytotoxicity in exhausted NK cells. We found that excessive activation of the NKG2A/HLA-E axis was associated with PI3K-AKT pathway inhibition, and blocking the NKG2A/HLA-E interaction or knocking out NKG2A restored AKT phosphorylation in exhausted NK cells. In summary, AML cells drive NK cell exhaustion through overactivation of the NKG2A/HLA-E axis and suppression of the PI3K-AKT pathway. Targeting the NKG2A/HLA-E axis represents a promising therapeutic approach to restore PI3K-AKT signaling and reverse NK cell exhaustion.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"40 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143909876","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":"Single-cell transcriptomic analysis reveals gut microbiota-immunotherapy synergy through modulating tumor microenvironment","authors":"Minyuan Cao, Yun Deng, Qing Hao, Huayun Yan, Quan-Lin Wang, Chunyan Dong, Jing Wu, Yajiao He, Li-Bin Huang, Xuyang Xia, Yongchao Gao, Hai-Ning Chen, Wei-Han Zhang, Yan-Jing Zhang, Xiaozhen Zhuo, Lunzhi Dai, Hongbo Hu, Yong Peng, Feng Zhang, Zhaoqian Liu, Weihua Huang, Huiyuan Zhang, Li Yang, Yang Shu, Wei Zhang, Yan Zhang, Heng Xu","doi":"10.1038/s41392-025-02226-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02226-7","url":null,"abstract":"<p>The gut microbiota crucially regulates the efficacy of immune checkpoint inhibitor (ICI) based immunotherapy, but the underlying mechanisms remain unclear at the single-cell resolution. Using single-cell RNA sequencing and subsequent validations, we investigate gut microbiota-ICI synergy by profiling the tumor microenvironment (TME) and elucidating critical cellular interactions in mouse models. Our findings reveal that intact gut microbiota combined with ICIs may synergistically increase the proportions of <i>CD8</i>⁺, <i>CD4</i>⁺, and γδ T cells, reduce glycolysis metabolism, and reverse exhausted <i>CD8</i>⁺ T cells into memory/effector <i>CD8</i>⁺ T cells, enhancing antitumor response. This synergistic effect also induces macrophage reprogramming from M2 protumor <i>Spp1</i>⁺ tumor-associated macrophages (TAMs) to <i>Cd74</i>⁺ TAMs, which act as antigen-presenting cells (APCs). These macrophage subtypes show a negative correlation within tumors, particularly during fecal microbiota transplantation. Depleting <i>Spp1</i>⁺ TAMs in <i>Spp1</i> conditional knockout mice boosts ICI efficacy and T cell infiltration, regardless of gut microbiota status, suggesting a potential upstream role of the gut microbiota and highlighting the crucial negative impact of <i>Spp1</i>⁺ TAMs during macrophage reprogramming on immunotherapy outcomes. Mechanistically, we propose a γδ T cell-APC-<i>CD8</i>⁺ T cell axis, where gut microbiota and ICIs enhance Cd40lg expression on γδ T cells, activating Cd40 overexpressing APCs (e.g., <i>Cd74</i>⁺ TAMs) through CD40-CD40L-related NF-κB signaling and boosting <i>CD8</i>⁺ T cell responses via CD86-CD28 interactions. These findings highlight the potential importance of γδ T cells and <i>SPP1</i>-related macrophage reprogramming in activating <i>CD8</i>⁺ T cells, as well as the synergistic effect of gut microbiota and ICIs in immunotherapy through modulating the TME.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"2 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143897757","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}