Golgi Apparatus-Targeting Immunostimulant for Synergistic Activation of Antitumor Immunity via Pyroptosis Induction and PD-L1 Degradation.

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 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.