{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:16:33Z","timestamp":1788351393083,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"28","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["101200711"],"award-info":[{"award-number":["101200711"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Angew Chem Int Ed"],"published-print":{"date-parts":[[2026,7,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Targeted cancer immunotherapies typically depend on cell surface antigens to direct immune responses. However, many tumors either lack tumor\u2010specific markers or downregulate their expression, limiting the applicability of antigen\u2010directed strategies. In contrast, tumor acidosis represents a nearly universal hallmark of solid cancers, arising from dysregulated metabolism that acidifies the extracellular tumor microenvironment (TME). Here, we leverage this feature to develop Marker\u2010Agnostic Tumor Anchoring Chimeras (MATRACs), pH\u2010sensitive fusion proteins that mediate ternary complex formation between cancer cells and immune effector cells in an antigen\u2010independent manner. MATRACs harness the diphtheria toxin translocation domain (tdDT), whose pH\u2010dependent conformational switch drives membrane insertion, allowing tdDT and its Fc\u2010fused form (tdDT\u2010Fc) to anchor selectively to cells in TME\u2010like acidity while remaining inactive at physiological pH. To demonstrate pH\u2010dependent immune activation, we designed a fluorescein\u2010tagged tdDT\u2010Fc variant that anchors to tumor cells in acidic conditions and presents a synthetic epitope enabling recruitment of antifluorescein CAR T cells. These findings establish tdDT\u2010based MATRACs as a modular, TME\u2010responsive platform for antigen\u2010agnostic immune engagement and support their potential for next\u2010generation pH\u2010targeted immunotherapies.<\/jats:p>","DOI":"10.1002\/anie.202525715","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T07:28:42Z","timestamp":1779434922000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Marker\u2010Agnostic Tumor Anchoring Chimeras Enable pH\u2010Gated Immune Engagement"],"prefix":"10.1002","volume":"65","author":[{"given":"Heleen","family":"Lauwers","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, Ghent University, Belgium Cancer Research Institute Ghent (CRIG)  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"De Baere","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ghent University, Belgium Cancer Research Institute Ghent (CRIG)  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilke","family":"Aernout","sequence":"additional","affiliation":[{"name":"Ghent Research Group on Nanomedicines Ghent University Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Cappellesso","sequence":"additional","affiliation":[{"name":"Lab of Dendritic Cell Biology and Cancer Immunotherapy, VIB Center for Inflammation Research; Brussels, Belgium; Lab of Cellular and Molecular Immunology, Brussels Center For Immunology Vrije Universiteit Brussel (VUB)  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stijn","family":"De Munter","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Sciences, Ghent University, Ghent, Belgium Cancer Research Institute Ghent (CRIG)  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demi","family":"Defreyne","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ghent University, Belgium Cancer Research Institute Ghent (CRIG)  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Neeser","sequence":"additional","affiliation":[{"name":"The Raymond G. Perelman Center For Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomasz M.","family":"Grzywa","sequence":"additional","affiliation":[{"name":"The Raymond G. Perelman Center For Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Bosteels","sequence":"additional","affiliation":[{"name":"Laboratory of Immunoregulation and Mucosal Immunology, VIB\u2010UGent Center for Inflammation Research, Ghent, Belgium; Department of Internal Medicine and Pediatrics Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Vandekerckhove","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Sciences, Ghent University, Ghent, Belgium Cancer Research Institute Ghent (CRIG)  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ine","family":"Lentacker","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Ghent University, Belgium Cancer Research Institute Ghent (CRIG)  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyuan","family":"Ma","sequence":"additional","affiliation":[{"name":"The Raymond G. Perelman Center For Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA; Abramson Cancer Center University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jurgen","family":"Haustraete","sequence":"additional","affiliation":[{"name":"VIB Protein Core, VIB\u2010UGent Center for Inflammation, Ghent, Belgium; Department for Medical Molecular Biology Ghent University  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Savvas N.","family":"Savvides","sequence":"additional","affiliation":[{"name":"Unit For Structural Biology, Department of Biochemistry and Microbiology, Ghent University VIB\u2010UGent Center for Inflammation  Ghent 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