Receptor-Triggered Peptide Self-Assembly Enables Multivalent Recruitment of Endogenous Antibodies for Cancer Immunotherapy.

Monoclonal antibody-based immunotherapies have achieved remarkable clinical success but remain limited by variable patient responses, immune-related toxicities, and the complexity of antibody production. Antibody-recruiting molecules (ARMs) offer an alternative strategy by harnessing endogenous antibodies to induce immune-mediated tumor clearance; however, their therapeutic efficacy is often constrained by insufficient antibody recruitment arising from weak hapten-antibody interactions. Here we report a receptor-triggered supramolecular assembly strategy that converts monovalent antibody recruiters into multivalent immunotherapeutic platforms directly on cancer cell surfaces. An EGFR-targeting peptide (GE11) was conjugated with a dinitrophenyl (DNP) hapten and a short self-assembly motif to afford a monomeric construct that undergoes EGFR-mediated in situ self-assembly into fibrillar networks on EGFR-overexpressing cells. This receptor-guided supramolecular transformation generates a high-density multivalent display of haptens on the cell membrane, enabling efficient recruitment of endogenous anti-DNP antibodies. The resulting assemblies induce potent complement-dependent cytotoxicity (CDC) against EGFR-positive cancer cells in vitro and produce significant antitumor efficacy in tumor-bearing mouse models with minimal systemic toxicity. This work establishes receptor-mediated peptide self-assembly as a general supramolecular strategy for transforming monovalent antibody recruiters into multivalent immunotherapeutic platforms, providing a new framework for the design of selective ARMs for cancer immunotherapy.