Chimeric antigen receptor (CAR)-T cell therapy exerts limited therapeutic efficacy in solid tumors including digestive tract cancer (DTC), which is largely attributable to the suppressive tumor microenvironment (TME) and the functional deficits of CAR-T cells. Herein, we generated fourth-generation CAR-T cells engineered to target Claudin18.2 (CLDN18.2) with concurrent secretion of IL-7 and XCL1, which are designated as ExCAR-T cells (also named RD07 cells in a clinical trial). The preclinical results demonstrated the remarkable and enduring suppressive effects of ExCAR-T cells on DTC growth in murine models through activating both the inherent of the administered CAR-T cells and robust endogenous immune cells anti-tumor response. Furthermore, we performed a clinical investigation for previous systemic treatment failed patients with DTC. RD07 therapy was well tolerated, and 7 out of 10 patients exhibited tumor regression; this effect was particularly evident in patients exhibiting moderate to high CLDN18.2 expression (DCR of 100%). Finally, single-cell RNA (scRNA) sequencing combined with spatial landscape profiling revealed that RD07 has antitumor effects and activates endogenous immune cells within the TME. Concomitantly, enhanced cytotoxic activity of CAR-T cells and expanded T cell receptor (TCR) clonotypes were detected in patients with a partial response (PR). Taken together, present data demonstrate the therapeutic efficacy and safety of RD07 in our study and highlight its ability to both exert antitumor effects and remodel the TME. These findings support RD07 as an innovative CAR-T cell therapy for DTC.
{"title":"Efficacy and immunomodulatory effect of Claudin18.2-specific IL-7/XCL1 armored CAR-T cells in digestive tract cancer: preclinical and clinical analysis.","authors":"Xuan Zhao,Jinyan Liu,Zhen Zhang,Yali Zhou,Shuiling Jin,Hong Zong,Feng Wang,Min Song,Yali Zhong,Qinglong Li,Bo Pei,Yong Yu,Ming Gao,Wengang Ge,Lu Han,Jiangtao Ren,Yi Zhang","doi":"10.1038/s41392-026-02621-8","DOIUrl":"https://doi.org/10.1038/s41392-026-02621-8","url":null,"abstract":"Chimeric antigen receptor (CAR)-T cell therapy exerts limited therapeutic efficacy in solid tumors including digestive tract cancer (DTC), which is largely attributable to the suppressive tumor microenvironment (TME) and the functional deficits of CAR-T cells. Herein, we generated fourth-generation CAR-T cells engineered to target Claudin18.2 (CLDN18.2) with concurrent secretion of IL-7 and XCL1, which are designated as ExCAR-T cells (also named RD07 cells in a clinical trial). The preclinical results demonstrated the remarkable and enduring suppressive effects of ExCAR-T cells on DTC growth in murine models through activating both the inherent of the administered CAR-T cells and robust endogenous immune cells anti-tumor response. Furthermore, we performed a clinical investigation for previous systemic treatment failed patients with DTC. RD07 therapy was well tolerated, and 7 out of 10 patients exhibited tumor regression; this effect was particularly evident in patients exhibiting moderate to high CLDN18.2 expression (DCR of 100%). Finally, single-cell RNA (scRNA) sequencing combined with spatial landscape profiling revealed that RD07 has antitumor effects and activates endogenous immune cells within the TME. Concomitantly, enhanced cytotoxic activity of CAR-T cells and expanded T cell receptor (TCR) clonotypes were detected in patients with a partial response (PR). Taken together, present data demonstrate the therapeutic efficacy and safety of RD07 in our study and highlight its ability to both exert antitumor effects and remodel the TME. These findings support RD07 as an innovative CAR-T cell therapy for DTC.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"6 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147381233","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}
Pub Date : 2026-03-06DOI: 10.1038/s41392-026-02629-0
Aftab Alam, Shyamananda Singh Mayengbam, Scott I Abrams, Jun Qu, Prasenjit Dey
{"title":"Exocyst complex regulates fungal-mediated IL-33 release from cancer cells","authors":"Aftab Alam, Shyamananda Singh Mayengbam, Scott I Abrams, Jun Qu, Prasenjit Dey","doi":"10.1038/s41392-026-02629-0","DOIUrl":"https://doi.org/10.1038/s41392-026-02629-0","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"198 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350815","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}
Pub Date : 2026-03-06DOI: 10.1038/s41392-025-02532-0
Xiangqi Chen,Jinhang Zhang,Ling Guo,Chuan Wu,Jingyue Zhou,Mingzhu Xu,Li Mo,Yanping Li,Jinhan He
Fibrosis is a maladaptive pathophysiological process characterized by excessive deposition of extracellular matrix resulting from dysregulated tissue repair responses. Fibrosis can affect nearly all organ systems, such as the lung, heart, liver, and kidney. Persistent fibrotic remodeling leads to architectural distortion, loss of function, organ failure, and ultimately increased mortality. These devastating outcomes highlight the urgent need for effective antifibrotic therapies. Advances in multiomics technologies have revealed that fibrosis represents a dynamic alteration spanning the molecular, cellular, microenvironmental, and organ levels. Despite impressive progress in our understanding of fibrogenesis over recent years, a substantial translational gap remains between identifying potential antifibrotic targets and translating this theoretical knowledge into effective human therapies. To further understand pathogenesis and facilitate the development of novel antifibrotic drugs, this review summarizes crucial milestones in fibrosis research, elaborates on organ-specific pathogenic mechanisms, and details the phenotypic and functional changes in critical cellular players, including parenchymal cells, fibroblasts, endothelial cells, and immune cells. Furthermore, this review outlines the key signaling pathways implicated in the pathogenesis of fibrosis, provides a comprehensive overview of relevant clinical trials, and discusses promising future research directions, including cross-organ multiomics integration, chimeric antigen receptor therapy, and artificial intelligence technology applications.
{"title":"Decoding organ fibrosis: mechanistic insights and emerging therapeutic strategies.","authors":"Xiangqi Chen,Jinhang Zhang,Ling Guo,Chuan Wu,Jingyue Zhou,Mingzhu Xu,Li Mo,Yanping Li,Jinhan He","doi":"10.1038/s41392-025-02532-0","DOIUrl":"https://doi.org/10.1038/s41392-025-02532-0","url":null,"abstract":"Fibrosis is a maladaptive pathophysiological process characterized by excessive deposition of extracellular matrix resulting from dysregulated tissue repair responses. Fibrosis can affect nearly all organ systems, such as the lung, heart, liver, and kidney. Persistent fibrotic remodeling leads to architectural distortion, loss of function, organ failure, and ultimately increased mortality. These devastating outcomes highlight the urgent need for effective antifibrotic therapies. Advances in multiomics technologies have revealed that fibrosis represents a dynamic alteration spanning the molecular, cellular, microenvironmental, and organ levels. Despite impressive progress in our understanding of fibrogenesis over recent years, a substantial translational gap remains between identifying potential antifibrotic targets and translating this theoretical knowledge into effective human therapies. To further understand pathogenesis and facilitate the development of novel antifibrotic drugs, this review summarizes crucial milestones in fibrosis research, elaborates on organ-specific pathogenic mechanisms, and details the phenotypic and functional changes in critical cellular players, including parenchymal cells, fibroblasts, endothelial cells, and immune cells. Furthermore, this review outlines the key signaling pathways implicated in the pathogenesis of fibrosis, provides a comprehensive overview of relevant clinical trials, and discusses promising future research directions, including cross-organ multiomics integration, chimeric antigen receptor therapy, and artificial intelligence technology applications.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"16 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147359261","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}
Pub Date : 2026-03-05DOI: 10.1038/s41392-026-02595-7
Jung Hwa Lim, Seon Ju Mun, Hyun Mi Kang, Won Dong Yu, Soo Jin Oh, Ji-Yoon Lee, Ye Seul Son, Sugi Lee, Dae Soo Kim, Jaeseo Lee, Su Jeong Kim, Hyun-Soo Cho, Myung Jin Son, Mi-Young Son, Cho-Rok Jung
Effective precision oncology demands integration of pharmacokinetics/pharmacodynamics (PK/PD) profiling with tumor-specific genomic features. Here, we present a personalized treatment model using a patient-derived Networking Organoid Culture System (NOCS) composed of intestinal, liver, and kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of an NF1-mutant breast cancer patient. This multi-organoid system enabled individualized assessment of drug absorption, distribution, metabolism, and excretion. Integrative genomic and pathway analyses uncovered therapeutic vulnerabilities, including responsiveness to a novel exon skipping therapy targeting NF1. PK/PD-guided screening on the NOCS prioritized Paxalisib, which, when combined with the exon skipping approach, demonstrated synergistic anticancer efficacy in patient-derived tumor models. These findings establish a clinically relevant framework that integrates multi-organ PK/PD modeling with genotype-driven therapeutic strategies, highlighting the potential of combining targeted gene correction with small-molecule therapy for personalized treatment. This platform offers broad applicability in precision oncology and drug development across diverse genetic contexts.
{"title":"Personalized pharmacokinetic–pharmacodynamic guided therapy via an induced pluripotent stem cell–derived multi-organoid platform in NF1-mutant breast cancer","authors":"Jung Hwa Lim, Seon Ju Mun, Hyun Mi Kang, Won Dong Yu, Soo Jin Oh, Ji-Yoon Lee, Ye Seul Son, Sugi Lee, Dae Soo Kim, Jaeseo Lee, Su Jeong Kim, Hyun-Soo Cho, Myung Jin Son, Mi-Young Son, Cho-Rok Jung","doi":"10.1038/s41392-026-02595-7","DOIUrl":"https://doi.org/10.1038/s41392-026-02595-7","url":null,"abstract":"Effective precision oncology demands integration of pharmacokinetics/pharmacodynamics (PK/PD) profiling with tumor-specific genomic features. Here, we present a personalized treatment model using a patient-derived Networking Organoid Culture System (NOCS) composed of intestinal, liver, and kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of an NF1-mutant breast cancer patient. This multi-organoid system enabled individualized assessment of drug absorption, distribution, metabolism, and excretion. Integrative genomic and pathway analyses uncovered therapeutic vulnerabilities, including responsiveness to a novel exon skipping therapy targeting NF1. PK/PD-guided screening on the NOCS prioritized Paxalisib, which, when combined with the exon skipping approach, demonstrated synergistic anticancer efficacy in patient-derived tumor models. These findings establish a clinically relevant framework that integrates multi-organ PK/PD modeling with genotype-driven therapeutic strategies, highlighting the potential of combining targeted gene correction with small-molecule therapy for personalized treatment. This platform offers broad applicability in precision oncology and drug development across diverse genetic contexts.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"11 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346790","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}
Pub Date : 2026-03-05DOI: 10.1038/s41392-026-02596-6
Min Mu, Hui Li, Bo Chen, Rangrang Fan, Kunhong Zhong, Guoqing Wang, Chenqian Feng, Nianyong Chen, Gang Guo, Aiping Tong, Bingwen Zou
The broader clinical application of Bispecific T-cell engagers (BiTEs) is hindered by their short half-life, on-target off-tumor toxicity, and limited therapeutic effect for solid tumors. Herein, we constructed a bimetallic-enriched triple-kill nanobomb manganese/Co2+-dopamine@BiTE/HPT (MnO2/Co-DA@BiTE/HPT) based on metal-polyphenol to improve the immunosuppressive tumor microenvironment by activating innate and adaptive immunity, thereby enhancing the treatment efficacy of BiTEs (PD-L1/CD3). A hyaluronic acid-modified PD-L1 aptamer (HPT) was introduced to improve the active targeting of the nanobombs and bind with PD-L1 overexpressing colorectal cancer. Bimetallic (Mn2+/Co2+) activated the STING pathway; simultaneously, photothermal therapy (PTT) induces DNA fragmentation to cooperate with bimetallic to amplify the STING signal to “heat” the “cold” tumor microenvironment. The “hot” tumor with a large amount of T-cell infiltration facilitated BiTE recruitment of T cells to kill tumor cells. Furthermore, the efficient therapeutic potency of the triple-kill nanobombs (STING, BiTE, and PTT) was determined in subcutaneous colorectal cancer, distal, lung metastasis, and postoperative recurrence models, which indicated that MnO2/Co-DA@BiTE/HPT could improve the immune microenvironment, produce long-term immune memory, inhibit tumor growth, and prevent tumor recurrence and metastasis.
{"title":"Unleashing the potential of bimetallic nanobomb-mediated STING pathway to enhance bispecific T-cell engager against colorectal cancer photo-immunotherapy","authors":"Min Mu, Hui Li, Bo Chen, Rangrang Fan, Kunhong Zhong, Guoqing Wang, Chenqian Feng, Nianyong Chen, Gang Guo, Aiping Tong, Bingwen Zou","doi":"10.1038/s41392-026-02596-6","DOIUrl":"https://doi.org/10.1038/s41392-026-02596-6","url":null,"abstract":"The broader clinical application of Bispecific T-cell engagers (BiTEs) is hindered by their short half-life, on-target off-tumor toxicity, and limited therapeutic effect for solid tumors. Herein, we constructed a bimetallic-enriched triple-kill nanobomb manganese/Co2+-dopamine@BiTE/HPT (MnO2/Co-DA@BiTE/HPT) based on metal-polyphenol to improve the immunosuppressive tumor microenvironment by activating innate and adaptive immunity, thereby enhancing the treatment efficacy of BiTEs (PD-L1/CD3). A hyaluronic acid-modified PD-L1 aptamer (HPT) was introduced to improve the active targeting of the nanobombs and bind with PD-L1 overexpressing colorectal cancer. Bimetallic (Mn2+/Co2+) activated the STING pathway; simultaneously, photothermal therapy (PTT) induces DNA fragmentation to cooperate with bimetallic to amplify the STING signal to “heat” the “cold” tumor microenvironment. The “hot” tumor with a large amount of T-cell infiltration facilitated BiTE recruitment of T cells to kill tumor cells. Furthermore, the efficient therapeutic potency of the triple-kill nanobombs (STING, BiTE, and PTT) was determined in subcutaneous colorectal cancer, distal, lung metastasis, and postoperative recurrence models, which indicated that MnO2/Co-DA@BiTE/HPT could improve the immune microenvironment, produce long-term immune memory, inhibit tumor growth, and prevent tumor recurrence and metastasis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"95 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346862","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}
Pub Date : 2026-03-04DOI: 10.1038/s41392-025-02556-6
Yi Zhang,Yanqi Han,Ying Sun,Longhui Hao,Yue Gao,Jun Ye,Hongliang Wang,Tiantai Zhang,Yuling Liu,Yanfang Yang
Osteoarthritis (OA) is a debilitating joint disorder that causes chronic pain, inflammation, and detrimental bone alterations. Despite significant advances in understanding OA pathogenesis, current therapeutic strategies remain inadequate in halting disease progression or providing effective pain relief, highlighting unmet clinical needs. Recent insights into OA nociceptive pathways, inflammatory mediators, and organelle dysfunction have revealed promising therapeutic targets. Specifically, OA progression is driven by mitochondrial dysfunction (marked by accumulated damaged mitochondria with excessive ROS production and impaired ATP synthesis), lysosomal destabilization (due to persistent hydroxyapatite digestion causing acidification loss, membrane permeabilization, and chondrocyte apoptosis), and unresolved ER stress (resulting from compensatory protein overproduction that exacerbates cartilage degradation). In this review, we aim to provide a comprehensive exploration of the nociceptive pathways linking the knee joint to the central nervous system, shedding light on the mechanisms underlying OA-associated pain. We further analyzed pathological changes in bone architecture and chondrocytes, emphasizing the synergistic roles of inflammatory cytokines and organelle-specific dysfunctions. Building on these mechanistic insights, we delineate emerging pharmacological strategies designed to concurrently address inflammatory cascades, restore organelle homeostasis (via mitophagy potentiation, lysosomal integrity preservation, and ER stress alleviation), and attenuate nociceptive signaling-thereby establishing a multimodal therapeutic paradigm to ameliorate both structural degeneration and clinical manifestations of OA. We also highlight advanced organelle-targeted drug delivery systems designed to increase the therapeutic efficacy and stability of these treatments. Collectively, these advancements provide a framework for novel OA interventions.
{"title":"Osteoarthritis: molecular pathogenesis and potential therapeutic options.","authors":"Yi Zhang,Yanqi Han,Ying Sun,Longhui Hao,Yue Gao,Jun Ye,Hongliang Wang,Tiantai Zhang,Yuling Liu,Yanfang Yang","doi":"10.1038/s41392-025-02556-6","DOIUrl":"https://doi.org/10.1038/s41392-025-02556-6","url":null,"abstract":"Osteoarthritis (OA) is a debilitating joint disorder that causes chronic pain, inflammation, and detrimental bone alterations. Despite significant advances in understanding OA pathogenesis, current therapeutic strategies remain inadequate in halting disease progression or providing effective pain relief, highlighting unmet clinical needs. Recent insights into OA nociceptive pathways, inflammatory mediators, and organelle dysfunction have revealed promising therapeutic targets. Specifically, OA progression is driven by mitochondrial dysfunction (marked by accumulated damaged mitochondria with excessive ROS production and impaired ATP synthesis), lysosomal destabilization (due to persistent hydroxyapatite digestion causing acidification loss, membrane permeabilization, and chondrocyte apoptosis), and unresolved ER stress (resulting from compensatory protein overproduction that exacerbates cartilage degradation). In this review, we aim to provide a comprehensive exploration of the nociceptive pathways linking the knee joint to the central nervous system, shedding light on the mechanisms underlying OA-associated pain. We further analyzed pathological changes in bone architecture and chondrocytes, emphasizing the synergistic roles of inflammatory cytokines and organelle-specific dysfunctions. Building on these mechanistic insights, we delineate emerging pharmacological strategies designed to concurrently address inflammatory cascades, restore organelle homeostasis (via mitophagy potentiation, lysosomal integrity preservation, and ER stress alleviation), and attenuate nociceptive signaling-thereby establishing a multimodal therapeutic paradigm to ameliorate both structural degeneration and clinical manifestations of OA. We also highlight advanced organelle-targeted drug delivery systems designed to increase the therapeutic efficacy and stability of these treatments. Collectively, these advancements provide a framework for novel OA interventions.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"32 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350816","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}
Immunotherapy with immune checkpoint blockade (ICB) in epithelial ovarian carcinoma (EOC) shows limited clinical benefit only for a small subset of patients. Overall response rates are low, so that overcoming immunotherapy resistance and improved stratification are key. In this study, we investigated the immunometabolic landscape of EOC with a focus on omental metastases, identifying lipid-laden macrophages as central elements for actionable therapeutic vulnerabilities and giving rise to biomarkers for improved patient stratification. Using patient-derived explants, we demonstrated a functional dichotomy inside the typically lipid-rich microenvironment of omental metastases: augmented maintenance of effector T cell function, while lipid uptake and processing by tumor-associated macrophages (TAMs) induces oxidative stress-dependent signaling programs, which drive macrophage dysfunction and immune suppression. Pharmacological modulation of lipid-driven signaling pathways through CCR5 inhibition (inflammation modulation through maraviroc) or blockade of the lipid scavenger receptor CD36 reprograms TAMs, restores T cell activity, and enhances antitumor immune responses within lipid-rich tumor niches. Mechanistically, studies in humanized mouse models reveal that maraviroc-mediated CCR5 inhibition induces transcriptional programs associated with immune activation in stressed, lipid-laden human TAMs. Consistent with these mechanistic insights, we demonstrated that the specific immunometabolic niche in omental metastases is clinically associated with responsiveness to ICB. We propose a non-invasive radiomics and machine-learning-based analysis of imaging data to assess omental involvement for patient stratification.
{"title":"Harnessing lipid-driven immunometabolic pathways in omental metastases to enhance immunotherapy in patients with ovarian cancer.","authors":"Meggy Suarez-Carmona,Mareike Hampel,Xin-Wen Zhang,Alexandra Pöchmann,Silke A Grauling-Halama,Nektarios A Valous,Pornpimol Charoentong,Dyke Ferber,Jannis Wissfeld,Alicia Höflich,Stanislas Goriely,Aurélie Detavernier,Abdulkader Azouz,Anthony Rongvaux,Sven Zukunft,Ingrid Fleming,Jürgen G Okun,Vickie Baracos,Mathias Heikenwalder,Laurence Zitvogel,Xinyi Xu,Chenqi Xu,Michael Volkmar,Daniel Schraivogel,Lars Steinmetz,Junzo Hamanishi,Masaki Mandai,Matthias Gaida,Theresa Mokry,Johanna Nattenmüller,Oliver Sedlaczek,Nanna Monje,Roxana Schwab,Annette Hasenburg,Athanasios Mavratzas,Regina Johanna Boger,Frederik Marmé,Sarah Schott,Niels Halama","doi":"10.1038/s41392-026-02594-8","DOIUrl":"https://doi.org/10.1038/s41392-026-02594-8","url":null,"abstract":"Immunotherapy with immune checkpoint blockade (ICB) in epithelial ovarian carcinoma (EOC) shows limited clinical benefit only for a small subset of patients. Overall response rates are low, so that overcoming immunotherapy resistance and improved stratification are key. In this study, we investigated the immunometabolic landscape of EOC with a focus on omental metastases, identifying lipid-laden macrophages as central elements for actionable therapeutic vulnerabilities and giving rise to biomarkers for improved patient stratification. Using patient-derived explants, we demonstrated a functional dichotomy inside the typically lipid-rich microenvironment of omental metastases: augmented maintenance of effector T cell function, while lipid uptake and processing by tumor-associated macrophages (TAMs) induces oxidative stress-dependent signaling programs, which drive macrophage dysfunction and immune suppression. Pharmacological modulation of lipid-driven signaling pathways through CCR5 inhibition (inflammation modulation through maraviroc) or blockade of the lipid scavenger receptor CD36 reprograms TAMs, restores T cell activity, and enhances antitumor immune responses within lipid-rich tumor niches. Mechanistically, studies in humanized mouse models reveal that maraviroc-mediated CCR5 inhibition induces transcriptional programs associated with immune activation in stressed, lipid-laden human TAMs. Consistent with these mechanistic insights, we demonstrated that the specific immunometabolic niche in omental metastases is clinically associated with responsiveness to ICB. We propose a non-invasive radiomics and machine-learning-based analysis of imaging data to assess omental involvement for patient stratification.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346298","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}
Dendritic cells (DCs) regulate both innate and adaptive immunity during sepsis. Prostaglandins (PGs), small lipid molecules derived from arachidonic acid via COX enzymes, are crucial regulators of immune homeostasis and inflammation. However, their role in sepsis pathogenesis remains poorly defined. In this study, we identified a significant negative correlation between DC depletion and disease severity in patients with sepsis. Thromboxane (TX) A2 receptor (TP) expression was markedly reduced in the blood DCs of patients with sepsis. Patients with low DC-TP expression presented increased blood neutrophil counts and worsened disease severity. In murine models of sepsis induced by cecal ligation and puncture and lipopolysaccharide challenge, DC-specific TP deficiency exacerbated sepsis by promoting S100a8/a9-mediated neutrophil recruitment and, subsequently, neutrophil extracellular trap (NET) formation and lung injury. Genetic and pharmacological inhibition of the S100a8/a9-TLR4 axis protected TP-deficient mice from fatal sepsis. Mechanistically, TP signaling suppressed S100a8/a9 expression in DCs via PKCδ-Stat1 signaling, thereby restricting neutrophil infiltration and NET formation. Finally, the targeted activation of TP in DCs via the nanodrug DCpep-U-46619 effectively alleviated sepsis-induced lung injury in mice. These findings establish TP as a critical immunoregulatory receptor in DCs, highlighting its potential as a therapeutic target for sepsis.
树突状细胞（dc）在败血症期间调节先天免疫和适应性免疫。前列腺素是由花生四烯酸通过COX酶生成的小脂质分子，是免疫稳态和炎症的重要调节因子。然而，它们在脓毒症发病机制中的作用仍不明确。在这项研究中，我们发现脓毒症患者DC耗竭与疾病严重程度之间存在显著负相关。脓毒症患者血dc中血栓素（TX） A2受体（TP）表达明显降低。低DC-TP表达的患者外周血中性粒细胞计数增加，疾病严重程度加重。在盲肠结扎、穿刺和脂多糖刺激引起的小鼠脓毒症模型中，dc特异性TP缺乏通过促进S100a8/a9介导的中性粒细胞募集，进而促进中性粒细胞胞外陷阱（NET）的形成和肺损伤，加重了脓毒症。遗传和药理学抑制S100a8/a9-TLR4轴保护tp缺陷小鼠免于致死性败血症。在机制上，TP信号通过PKCδ-Stat1信号抑制dc中S100a8/a9的表达，从而限制中性粒细胞的浸润和NET的形成。最后，通过纳米药物dpep - u -46619靶向激活dc中的TP，有效地减轻了脓毒症诱导的小鼠肺损伤。这些发现证实TP在dc中是一种重要的免疫调节受体，突出了其作为脓毒症治疗靶点的潜力。
{"title":"Thromboxane receptor activation in dendritic cells mitigates sepsis by suppressing S100a8/a9-mediated neutrophil recruitment.","authors":"Ronglu Du,Ting Pan,Yuhan Wang,Yan Fan,Qian Liu,Xixi Tao,Shumin Guo,Danyang Tian,Roger S-Y Foo,Keliang Xie,Jie Zhou,Yujun Shen,Ying Yu","doi":"10.1038/s41392-026-02592-w","DOIUrl":"https://doi.org/10.1038/s41392-026-02592-w","url":null,"abstract":"Dendritic cells (DCs) regulate both innate and adaptive immunity during sepsis. Prostaglandins (PGs), small lipid molecules derived from arachidonic acid via COX enzymes, are crucial regulators of immune homeostasis and inflammation. However, their role in sepsis pathogenesis remains poorly defined. In this study, we identified a significant negative correlation between DC depletion and disease severity in patients with sepsis. Thromboxane (TX) A2 receptor (TP) expression was markedly reduced in the blood DCs of patients with sepsis. Patients with low DC-TP expression presented increased blood neutrophil counts and worsened disease severity. In murine models of sepsis induced by cecal ligation and puncture and lipopolysaccharide challenge, DC-specific TP deficiency exacerbated sepsis by promoting S100a8/a9-mediated neutrophil recruitment and, subsequently, neutrophil extracellular trap (NET) formation and lung injury. Genetic and pharmacological inhibition of the S100a8/a9-TLR4 axis protected TP-deficient mice from fatal sepsis. Mechanistically, TP signaling suppressed S100a8/a9 expression in DCs via PKCδ-Stat1 signaling, thereby restricting neutrophil infiltration and NET formation. Finally, the targeted activation of TP in DCs via the nanodrug DCpep-U-46619 effectively alleviated sepsis-induced lung injury in mice. These findings establish TP as a critical immunoregulatory receptor in DCs, highlighting its potential as a therapeutic target for sepsis.","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"172 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147329208","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}
Pub Date : 2026-03-03DOI: 10.1038/s41392-026-02593-9
Eric Schoger,Rosa Kim,Federico Bleckwedel,Tomas Peralta,Laura Priesmeier,Janek Fischer,Laura Stengel,Cheila Rocha,Gabriela L Santos,Susanne Lutz,Etienne Boileau,Nina Baumgarten,Marcel H Schulz,Christoph Dieterich,Oliver J Müller,Lukas Cyganek,Alfredo Cabrera-Orefice,Hanna Eberl,Christoph Maack,Katrin Streckfuss-Bömeke,Mario Pavez-Giani,Shirin Doroudgar,Samuel T Sossalla,Laura C Zelarayán
Transcriptional activity perturbation holds promise for selectively modulating harmful transcriptional networks, but its therapeutic potential remains largely unexplored. We employed a network-based analysis of single-cell heart transcriptomes to identify transcription factor activities linked to pathological cardiomyocytes in vivo. This analysis revealed that transcriptional activity of Krüppel-like factor 15 (KLF15) exhibited the most significant change in pathological cardiomyocytes, characterized by less effective repression of disease-associated genes in stressed hearts, which correlated with reduced KLF15 expression. To restore KLF15 activity, we utilized CRISPR/nuclease-dead (d)Cas9-based transcriptional enhancement (CRISPRa) in cardiomyocytes, which effectively abolished fetal reprogramming by simultaneously suppressing pathological gene expression and restoring metabolic homeostasis under sustained stress conditions. Furthermore, we identified a novel cell-nonautonomous anti-fibrotic effect mediated by cardiomyocyte-fibroblast crosstalk, and revealed the contribution of KLF15-dependent Alpha-2-glycoprotein 1, zinc-binding (AZGP1) regulation in this process. We also elucidated the upstream mechanisms of KLF15 regulation, highlighting its role as a cell-specific downstream target of the broad TGF-β canonical signaling pathway, along with its downstream-dependent mechanisms in human cardiomyocytes. Finally, to enhance the therapeutic potential of this approach, we engineered and validated an adeno-associated viral (AAV) vector with a small CRISPRa system for endogenous regulation in human cardiomyocytes suitable for clinical applications. Overall, we elucidated a regulatory circuit involving TGF-β, KLF15, and AZGP1, which coordinates critical pathological responses through cellular crosstalk between cardiomyocytes and fibroblasts. Importantly, we demonstrated the efficacy of CRISPRa as an epigenetic intervention restoring a critical transcriptional function disrupted in non-genetic heart failure. This approach provides a promising blueprint for future adaptation targeting additional non-hereditary pathologies.
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