{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["21(3)"],"submitter":["Liang S"],"pubmed_abstract":["Despite the tremendous progress of chimeric antigen receptor T (CAR-T) cell therapy in hematological malignancies, their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment (TME) and systemic toxicity caused by excessive cytokine release. As a key regulator of the immunosuppressive TME, TGF-β promotes cytokine synthesis via the NF-κB pathway. Here, we coexpressed SMAD7, a suppressor of TGF-β signaling, with a HER2-targeted CAR in engineered T cells. These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion, which enabled sustained tumoricidal capacity after continuous antigen exposure. Moreover, SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells. Mechanistically, SMAD7 downregulated TGF-β receptor I and abrogated the interplay between the TGF-β and NF-κB pathways in CAR-T cells. As a result, these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β. SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids. Therefore, our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors."],"journal":["Cellular & molecular immunology"],"pagination":["213-226"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10901810"],"repository":["biostudies-literature"],"pubmed_title":["SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors."],"pmcid":["PMC10901810"],"pubmed_authors":["Liang S","Li J","Meng R","Zheng R","Han Y","Yang A","Jia L","Zhao X","Wang P","Dong H","Zhang Y","Yan B","Wang Y","Zuo B"],"additional_accession":[]},"is_claimable":false,"name":"SMAD7 expression in CAR-T cells improves persistence and safety for solid tumors.","description":"Despite the tremendous progress of chimeric antigen receptor T (CAR-T) cell therapy in hematological malignancies, their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment (TME) and systemic toxicity caused by excessive cytokine release. As a key regulator of the immunosuppressive TME, TGF-β promotes cytokine synthesis via the NF-κB pathway. Here, we coexpressed SMAD7, a suppressor of TGF-β signaling, with a HER2-targeted CAR in engineered T cells. These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion, which enabled sustained tumoricidal capacity after continuous antigen exposure. Moreover, SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells. Mechanistically, SMAD7 downregulated TGF-β receptor I and abrogated the interplay between the TGF-β and NF-κB pathways in CAR-T cells. As a result, these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β. SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids. Therefore, our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-05-29T11:37:58.386Z","creation":"2025-04-04T09:08:39.251Z"},"accession":"S-EPMC10901810","cross_references":{"pubmed":["38177245"],"doi":["10.1038/s41423-023-01120-y"]}}