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The study introduces a synapse-stabilizing receptor (SSR) that selectively boosts cytotoxic signaling and immune synapse formation by amplifying CD3ζ signaling after binding a secondary tumor antigen. A modified LAT endodomain increases Ca2+ flux, MAPK and NF-kB activation, synapse maturation, and degranulation, while removing LAT177 C-terminal amino acids reduces SSR-driven cytotoxicity. In acute myeloid leukemia models, a CD38-targeting SSR strengthens killing of antigen-low cells via CLL1-specific CAR and survivin-specific TCR without harming normal CD38+ tissues.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/enhancing-car-and-tcr-mediated-targeting-of-cancer-via-an-immune-synapse-stabilizing-receptor/346383/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/enhancing-car-and-tcr-mediated-targeting-of-cancer-via-an-immune-synapse-stabilizing-receptor/346383.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why do engineered CAR T-cell therapies often underperform against some cancers?","Question",{"text":112,"@type":113},"Heterogeneous antigen expression limits clinical benefit and supports treatment resistance through antigen escape. Partial antigen downregulation can be enough to evade adoptive cell therapy.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What is the role of the immune synapse-stabilizing receptor (SSR) in the study?",{"text":117,"@type":113},"SSR is designed to selectively enhance cytotoxic signaling and immune synapse formation by amplifying CD3ζ signaling from CAR or TCR engagement, improving Ca2+ flux, MAPK/NF-kB activation, and degranulation.",{"name":119,"@type":110,"acceptedAnswer":120},"How do the authors reduce unwanted SSR-mediated cytotoxicity?",{"text":121,"@type":113},"They remove C-terminal amino acids 178-233 in the LAT endodomain (LAT177), which was necessary to minimize SSR-mediated cytotoxicity.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},346383,1790160351,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":14,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":36},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","Article [https://doi.org/10.1038/s41467-025-65897-4](https://doi.org/10.1038/s41467-025-65897-4)  \nEnhancing CAR-and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor  \nReceived: 1 July 2024  \n\n| Accepted: 27 October 2025 |\n| --- |\n| |\n| Check for updates |\n\nChiou-Tsun Tsai 1,2, Jorge Ibanez-Vega3, Pan Yin1, Robert Teis3,4,  \nNorihiro Watanabe1, Tadahiro Honda1, Mikhail Valkov1, Peter J. Chockley 3,6, Lourdes Asenath Jimenez Madrigal1, Giedre Krenciute 3 &  \nMaksim Mamonkin 1,5,7   \nHeterogeneity in antigen expression on cancer cells limits clinical benefit of engineered T-cell therapies and underpins treatment resistance through antigen escape. Here, we present a strategy to improve recognition and lysis of tumors with suboptimal antigen expression through a separate engineered receptor that selectively boosts cytotoxic signaling and immune synapse formation. This synapse-stabilizing receptor (SSR) harbors a modified linker for activation of T cells (LAT) endodomain that amplifies CD3ζ signaling upon binding to a secondary tumor antigen resulting in an augmented Ca2+ flux, activation of MAPK and NF-kB signaling, maturation of immune synapse, and enhanced T-cell degranulation. Removing C-terminal amino acids 178-233 in the LAT endodomain (LAT177) was necessary to minimize SSR-mediated cytotoxicity. In models of acute myeloid leukemia, we show that a CD38-targeting SSR boosts cytolysis of antigen-low cancer cells via a C-type lectinlike molecule-1 (CLL1)-specificchimeric antigen receptor(CAR) anda survivinspecific T cell receptor (TCR). Unlike another CAR, SSR does not produce significant cytotoxicity against normal CD38+ tissues. Our study thus shows that SSR arming enhances targeting of antigenically heterogeneous cancers without compromising safety and selectivity of therapeutic T cells.  \nChimeric antigen receptor (CAR) T cells can effectively target cancers with high and uniform antigen expression and produce immense clinical benefit in patients with lymphoid malignancies. Other cancers, including acute myeloid leukemia (AML) and many solid tumors, remain resistant to CAR T-cell therapy, in part due to the lack of “safe”tumor-specific target antigens and high heterogeneity of their expression on cancer cells1–3. Unlike T-cell receptors (TCRs), which  \nrequire only several peptide-MHC molecules to trigger T-cell activation, CARs must engage a large number of target antigen molecules on the cell surface to initiate sufficient signaling4. This reduced sensitivity of CARs can help minimize damage to normal tissues that express the target antigen at a low level; however, it also underpins a major mechanism of cancer evasion from the adoptive cell therapy where partial antigen downregulation on tumor cells is sufficient to confer  \n1Center forCell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA. 2Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA. 3Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, USA. 4St. Jude Graduate School of Biomedical Sciences, Memphis, TN, USA. 5Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA. 6Present address: The Molecular Medicine and Therapeutics Department, The Ohio State University College of Medicine, Columbus, OH, USA. 7Present  \naddress: Columbia Initiative in Cell Therapy and Engineering, Department of Pediatrics, Columbia University, New York, NY, USA.  \n[e-mail:](e-mail: mm6947@cumc.columbia.edu)[ mm6947@cumc.columbia.edu](e-mail: mm6947@cumc.columbia.edu)  \nresistance to CAR T cells5,6. Similarly, downregulation of surface HLA levels has been associated with tumor relapse following allogeneic stem cell transplants and TCR T-cell therapy7. Combinatorial antigen targeting using several cytotoxic receptors (or a single receptor with two or more antigen binding domains) has been devised to overcome single antigen escape8,9. H","cbCaia0mm0D3JEaj","https://ap.wps.com/l/cbCaia0mm0D3JEaj","pdf",1857982,16,"English","# Introduction\n# Mechanistic rationale for LAT-based synapse stabilization\n# Results\n## CD38-SSR with LAT177 endodomain enhances antigen-specific cytolysis\n## Safety and selectivity assessment","[{\"question\":\"Why do engineered CAR T-cell therapies often underperform against some cancers?\",\"answer\":\"Heterogeneous antigen expression limits clinical benefit and supports treatment resistance through antigen escape. Partial antigen downregulation can be enough to evade adoptive cell therapy.\"},{\"question\":\"What is the role of the immune synapse-stabilizing receptor (SSR) in the study?\",\"answer\":\"SSR is designed to selectively enhance cytotoxic signaling and immune synapse formation by amplifying CD3ζ signaling from CAR or TCR engagement, improving Ca2+ flux, MAPK/NF-kB activation, and degranulation.\"},{\"question\":\"How do the authors reduce unwanted SSR-mediated cytotoxicity?\",\"answer\":\"They remove C-terminal amino acids 178-233 in the LAT endodomain (LAT177), which was necessary to minimize SSR-mediated cytotoxicity.\"}]","Enhancing CAR-and TCR-mediated targeting of cancer via an immune synapse-stabilizing receptor | PDF",1790061210]