Marker‐Agnostic Tumor Anchoring Chimeras Enable pH‐Gated Immune Engagement
Abstract
ABSTRACT Targeted cancer immunotherapies typically depend on cell surface antigens to direct immune responses. However, many tumors either lack tumor‐specific markers or downregulate their expression, limiting the applicability of antigen‐directed 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‐Agnostic Tumor Anchoring Chimeras (MATRACs), pH‐sensitive fusion proteins that mediate ternary complex formation between cancer cells and immune effector cells in an antigen‐independent manner. MATRACs harness the diphtheria toxin translocation domain (tdDT), whose pH‐dependent conformational switch drives membrane insertion, allowing tdDT and its Fc‐fused form (tdDT‐Fc) to anchor selectively to cells in TME‐like acidity while remaining inactive at physiological pH. To demonstrate pH‐dependent immune activation, we designed a fluorescein‐tagged tdDT‐Fc 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‐based MATRACs as a modular, TME‐responsive platform for antigen‐agnostic immune engagement and support their potential for next‐generation pH‐targeted immunotherapies.
Article Details
Authors (18)
Heleen Lauwers
Department of Pharmaceutics
Jamie De Baere
Department of Pharmaceutics Ghent University Ghent Belgium
Ilke Aernout
Ghent Research Group on Nanomedicines Ghent University Ghent Belgium
Federica Cappellesso
Lab of Cellular and Molecular Immunology Brussel Center for Immunology Vrije Universiteit Brussel Brussels Belgium
Stijn De Munter
Department of Diagnostic Sciences, Ghent University, Ghent, Belgium Cancer Research Institute Ghent (CRIG) Ghent Belgium
Demi Defreyne
Department of Pharmaceutics, Ghent University, Belgium Cancer Research Institute Ghent (CRIG) Ghent Belgium
Alexandra Neeser
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
Tomasz M. Grzywa
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
Victor Bosteels
Bart Vandekerckhove
Department of Diagnostic Sciences, Ghent University, Ghent, Belgium Cancer Research Institute Ghent (CRIG) Ghent Belgium
Ine Lentacker
Department of Pharmaceutics, Ghent University, Belgium Cancer Research Institute Ghent (CRIG) Ghent Belgium
Leyuan Ma
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
Jurgen Haustraete
VIB Protein Core, VIB‐UGent Center for Inflammation, Ghent, Belgium; Department for Medical Molecular Biology Ghent University Ghent Belgium
Savvas N. Savvides
Bart N. Lambrecht
Damya Laoui
Benoit Louage
Department of Pharmaceutics
Bruno G. De Geest
Department of Pharmaceutics