Similar Datasets
Project description:Denosumab Enhances antitumour Immunity by Suppressing SPP1 and Boosting Cytotoxic T Cells
| PRJNA1118819 | ENA
Project description:Chimeric antigen receptor-macrophage (CAR-M) possess the ability to migrate into the immunosuppressive tumour microenvironment (TME) of solid tumours and mediate phagocytosis. However, their efficacy is limited by challenges in precisely controlling tumour-specific immune activation and sustaining adaptive antitumour responses due to systemic off-target risks and inefficient antigen presentation. To overcome these limitations, we engineered an antigen prime-and-kill circuit, wherein tumour-specific synthetic Notch (syN) receptors locally induce the production of a kill antigen. This circuit enhances the precision of CAR-M while establishing self-sustaining antigen-presentation networks, amplifying tumour-specific T-cell adaptive immunity without eliciting systemic cytokine toxicity. To enable in situ CAR-M generation, we developed a macrophage-derived exosome-based delivery system to introduce syN-CAR genes into tumour-associated macrophages (TAMs), thereby generating syN-CAR-M within the TME. These engineered CAR-M actively sought and engulfed cancer cells while promoting a robust adaptive antitumour immune response in the TME in a murine tumour model. Our findings highlight that in situ induction of syN-CAR-M triggers a potent, tumour-specific adaptive immune response, offering a novel strategy for CAR-M-based immunotherapy and advancing precision cancer treatment by enhancing efficacy while minimizing systemic toxicity.
2026-03-01 | GSE293808 | GEO
Project description:Chimeric antigen receptor-macrophage (CAR-M) possess the ability to migrate into the immunosuppressive tumour microenvironment (TME) of solid tumours and mediate phagocytosis. However, their efficacy is limited by challenges in precisely controlling tumour-specific immune activation and sustaining adaptive antitumour responses due to systemic off-target risks and inefficient antigen presentation. To overcome these limitations, we engineered an antigen prime-and-kill circuit, wherein tumour-specific synthetic Notch (syN) receptors locally induce the production of a kill antigen. This circuit enhances the precision of CAR-M while establishing self-sustaining antigen-presentation networks, amplifying tumour-specific T-cell adaptive immunity without eliciting systemic cytokine toxicity. To enable in situ CAR-M generation, we developed a macrophage-derived exosome-based delivery system to introduce syN-CAR genes into tumour-associated macrophages (TAMs), thereby generating syN-CAR-M within the TME. These engineered CAR-M actively sought and engulfed cancer cells while promoting a robust adaptive antitumour immune response in the TME in a murine tumour model. Our findings highlight that in situ induction of syN-CAR-M triggers a potent, tumour-specific adaptive immune response, offering a novel strategy for CAR-M-based immunotherapy and advancing precision cancer treatment by enhancing efficacy while minimizing systemic toxicity.
2026-03-01 | GSE294490 | GEO
Project description:Chimeric antigen receptor-macrophage (CAR-M) possess the ability to migrate into the immunosuppressive tumour microenvironment (TME) of solid tumours and mediate phagocytosis. However, their efficacy is limited by challenges in precisely controlling tumour-specific immune activation and sustaining adaptive antitumour responses due to systemic off-target risks and inefficient antigen presentation. To overcome these limitations, we engineered an antigen prime-and-kill circuit, wherein tumour-specific synthetic Notch (syN) receptors locally induce the production of a kill antigen. This circuit enhances the precision of CAR-M while establishing self-sustaining antigen-presentation networks, amplifying tumour-specific T-cell adaptive immunity without eliciting systemic cytokine toxicity. To enable in situ CAR-M generation, we developed a macrophage-derived exosome-based delivery system to introduce syN-CAR genes into tumour-associated macrophages (TAMs), thereby generating syN-CAR-M within the TME. These engineered CAR-M actively sought and engulfed cancer cells while promoting a robust adaptive antitumour immune response in the TME in a murine tumour model. Our findings highlight that in situ induction of syN-CAR-M triggers a potent, tumour-specific adaptive immune response, offering a novel strategy for CAR-M-based immunotherapy and advancing precision cancer treatment by enhancing efficacy while minimizing systemic toxicity.
2026-03-01 | GSE295518 | GEO
Project description:The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2’3’-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.
2024-01-22 | GSE253724 | GEO
Project description:The efficacy of stimulator of interferon genes (STING) agonists is compromised by various factors, primarily inefficient intracellular delivery, low/lack of endogenous STING expression in many tumours and a complex balance between tumour control and progression. Here, we report a universal STING mimic (uniSTING) based on a polymeric architecture. The uniSTING activates STING signalling in a range of mouse and human cell types, independent of endogenous STING expression, and selectively stimulates tumour control IRF3/IFN-I pathways, but not tumour progression NF-κB pathways. Intratumoural or systemic injection of uniSTING-mRNA via lipid nanoparticles (LNP) results in potent anti-tumour efficacy across established and advanced metastatic tumour models, including triple negative breast cancer, lung cancer, melanoma and orthotopic/metastatic liver malignancies. Furthermore, uniSTING displays an effective antitumour response superior to 2’3’-cGAMP and ADU-S100. By favouring IRF3/IFN-I activity over the pro-inflammatory NF-κB signalling pathway, uniSTING promotes dendritic cell maturation and antigen specific CD8+ T cell responses. Extracellular vesicles released from uniSTING-treated tumour cells further sensitise dendritic cells via exosome containing miRNAs that reduced the immunosuppressive Wnt2b and a combination of LNP-uniSTING-mRNA with α-Wnt2b antibodies synergistically inhibit tumour growth and prolong animal survival. Collectively, these results demonstrate the LNP-mediated delivery of uniSTING-mRNA as a strategy to overcome the current STING therapeutic barriers, particularly for the treatment of multiple cancer types in which STING is downregulated or absent.
2024-01-24 | GSE253681 | GEO
Project description:The microbiome has a significant impact on immune health and response to immune-stimulating treatments, including cancer immunotherapy. However, the molecular mechanisms by which commensal microbes influence cancer immunology remain poorly understood. Here, we report on the discovery of a class of microbiome-derived metabolites called hydroxyphenyl propanoates (HPP) that enhance tumour immune surveillance in mice and synergize with immune checkpoint blockade (ICB) therapy. HPP molecules act as broad spectrum potentiators of innate immune signalling pathways in tumour-associated myeloid cells by promoting cleavage of the pore-forming protein gasdermin D (GSDMD), a critical effector of canonical and non-canonical inflammasome signalling. Heightened secretion of proinflammatory cytokines from HPP-treated myeloid cells, including IL-1β, promotes NF-κB activity within tumour-infiltrating leukocytes. This leads to heightened anticancer CD8 T cell accumulation, tumour regression, and long-term cancer control by immune checkpoint therapy in mice. Human peripheral blood mononuclear cells (PBMCs) respond to HPP treatment in a similar way. GSDMD cleavage also associates with a favourable response to ICB therapy in advanced stage melanoma patients. Taken together, our study uncovers a mechanism of microbiome-mediated modulation of host antitumour immunity that is modifiable and can be harnessed to enhance the efficacy of cancer immunotherapy. The proteomics part involved searching for hydroxuphenyl pyruvate interactors by using thermal profiling. TMT 10 plex and a method utilizing real-time search was used for quantification.
2025-05-06 | PXD045790 | Pride
Project description: Not available
| S-EPMC11365797 | biostudies-literature
Project description:Current chemotherapy or immunotherapy regimens for pancreatic cancer are limited. Although minimally invasive irreversible electroporation (IRE) ablation is a promising option for unresectable pancreatic cancers, the typical immunosuppressive tumour microenvironment promotes immune evasion and rapid tumour recurrence. Thus, triggering efficient amplification of endogenous adaptive antitumour immunity is critical for improving immunotherapy after ablation therapy. Here, we developed a hydrogel microsphere vaccine as an immune amplifier for post-ablation cancer immunotherapy. The vaccine acts as a general immune amplifier to trigger a rocket-like amplification of the cDC1-mediated antigen cross-presentation cascade, resulting in dramatic amplification of the antitumour immunity of endogenous CD8+ T cells. We also showed that the hydrogel microsphere vaccine promoted the transformation of pancreatic cancer from "cold" to "hot" tumours in a safe and efficient manner, significantly increased the survival of mice bearing orthotopic pancreatic tumours, and induced strong systemic antitumour immunity, which inhibited the growth of distant metastases.
2023-05-22 | GSE215417 | GEO
Project description: Not available
| S-EPMC10321278 | biostudies-literature