高尔基体靶向免疫刺激剂通过诱导焦亡和PD-L1降解协同激活抗肿瘤免疫

Abstract

The inherently low immunogenicity and immune evasion properties of breast cancer cells present major obstacles to the effective activation of antitumor immune responses. To overcome these challenges, we develop a Golgi apparatus-targeting immunostimulant (GA-IS) that synergistically enhances antitumor immunity through the induction of pyroptosis and degradation of PD-L1. GA-IS is based on an amphiphilic chimeric peptide (GA-Chip), which consists of a Golgi apparatus-targeting sequence (SDYQRL), a hydrophobic palmitic acid moiety, and the photosensitizer protoporphyrin IX (PpIX). This construct is co-formulated with the PD-L1 degrader dBET57 using DSPE-PEG 2000 to improve stability and systemic delivery. Upon accumulation in tumor cells, GA-IS enables precise drug delivery to the Golgi apparatus and elicits localized photodynamic effects, thereby inducing pyroptotic cell death and robust immunogenic cell death (ICD), ultimately enhancing tumor immunogenicity. Critically, GA-IS also downregulates PD-L1 expression via BRD4 degradation, effectively disrupting immune checkpoint signaling and restoring immune surveillance. As a result, GA-IS elicits a potent systemic immune response capable of suppressing both primary and metastatic breast cancer, while showing minimal systemic toxicity. This Golgi apparatus-targeting immunostimulant represents a promising strategy to reverse immune suppression in breast cancer and advance precision immunotherapy.