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.
Lauwers et al. (Fri,) studied this question.