Pyroptosis-Inducing Self-Adaptor to Potentiate Immune Checkpoint Blockade Therapy for Breast Cancer by Reeducating the Treatment-Recruited Macrophages

Abstract

Treatment-induced cell pyroptosis can improve the immunogenicity of breast cancer and enhance the efficacy of immune checkpoint blockade (ICB), but the resultant recruitment of immunosuppressive cells impedes the systemic anti-tumor immunity. Herein, a rationally designed self-adaptor (R@L-MRS17) is developed to initiate breast cancer cell pyroptosis and concomitantly reeducate the pyroptosis-recruited macrophages to enhance the ICB therapy. Of which, R@L-MRS17 promotes breast cancer-specific drug delivery through CD47 recognition, and enables the plasma membrane targeted photosensitizer insertion through hydrophobic and electrostatic interactions. Under light excitation, R@L-MRS17 produces reactive oxygen species (ROS) in situ to trigger cell pyroptosis, followed by the release of pro-inflammatory factors to recruit macrophages and improve tumor immunogenicity. Moreover, the acid responsiveness of R@L-MRS17 facilitates the release of R848 to polarize the infiltrated macrophages into M1 phenotype for active anti-tumor immunity. Additionally, R@L-MRS17 is capable of blocking CD47 to restore the recognition and phagocytosis behavior of M1-type macrophages against breast cancer cells. In short, the stepwise immune activation by R@L-MRS17 significantly suppresses the bilateral tumor growth and metastasis in combination with αPD-L1. This study provides a self-adaptable strategy to activate the immunological cascade, which may spatiotemporally amplify the immune responses for breast cancer.