A supramolecular self-assembled nanomaterial for synergistic therapy of immunosuppressive tumor

Triple negative breast cancer (TNBC) is an immunosuppressive "cold" tumor that lacks immune cell infiltration and activation, resulting in a poor response to immune checkpoint blockade (ICB) therapies. In addition, TNBC is poorly responsive to targeted therapies due to the absence of efficient molecular targets. A strategy that can block molecular signal transduction, stimulate immunogenicity, and activate the immune response is a promising approach to achieve ideal clinical benefit. Herein, we designed and synthesized an aggregation-induced emission luminogen (AIEgen)-conjugated self-assembling peptide that targets epidermal growth factor receptor (EGFR), named TPA-FFG-LA. TPA-FFG-LA peptides form nanoassemblies on the surface of EGFR-positive TNBC cells and are internalized into cells through endocytosis, which inhibit EGFR signaling transduction and provoke lysosomal membrane permeabilization (LMP). Upon light irradiation, the aggregated AIEgens produce massive reactive oxygen species (ROS) to exacerbate LMP and trigger immunogenic cell death (ICD), resulting in elimination of residual EGFR-negative tumor cells and exerting long-term antitumor effects. The in vitro and in vivo experiments verified that TPA-FFG-LA nanoassemblies suppress tumor growth, provoke immune cell activation and infiltration, and cause EGFR degradation and LMP. These results suggest that the combination of supramolecular assembly induced molecular targeting effects and lysosome dysfunction with ICD-stimulated immune activation is a plausible strategy for the efficient therapy of immunosuppressive TNBC.