An endoplasmic reticulum-targeting photodynamic AMPK agonist activates breast cancer immunotherapy through promoting immunogenic cell death and downregulation of PD-L1.

Most aggressive malignancies exhibit low immunogenicity, exacerbated by tumor immune evasion mechanisms that undermine immunotherapy efficacy. Studies indicate that AMP-activated protein kinase (AMPK) directly phosphorylates programmed cell death ligand 1 (PD-L1), promoting its degradation via the endoplasmic reticulum (ER)-associated pathway to restore and sustain cytotoxic T lymphocyte-mediated immunity. Here, we developed an ER-targeting photodynamic AMPK agonist (called PPFC) for breast cancer immunotherapy. PPFC comprised a chimeric peptide (PpIX-(PEG8-FFKDEL)) integrating a photosensitizer protoporphyrin IX (PpIX), a hydrophilic PEG8 linker, and the ER-targeting peptide sequence FFKDEL. The amphiphilic structure of the chimeric peptide facilitated its self-assembly into nanomicelles capable of encapsulating the AMPK agonist COH-SR4 (CS) within the chimeric peptide, forming PPFC. The findings demonstrated that this formulation enabled PPFC to accumulate in the ER of breast cancer cells, where photodynamic therapy (PDT)-generated reactive oxygen species (ROS) induced substantial ER stress, thereby amplifying immunogenic cell death (ICD) and improving tumor immunogenicity. Concurrent AMPK activation by PPFC downregulated PD-L1, counteracting immune evasion of breast cancer. The combined effects of PPFC triggered robust systemic anti-tumor immunity, eradicating primary tumors and lung metastases in 4T1 breast cancer-bearing mice. This subcellular-targeting photodynamic agonist offers a promising strategy to overcome immunosuppressive tumor microenvironments in metastatic cancers.