Chimeric Peptide Functionalized Immunostimulant to Orchestrate Photodynamic Immunotherapeutic Effect by PD-L1 Deglycosylation and CD47 Inhibition.

Breast cancer utilizes diverse immunosuppressive mechanisms to evade immune surveillance, thereby impairing immunotherapeutic effects. In this work, a chimeric peptide functionalized immunostimulant (designated as aGlyR) is fabricated to boost photodynamic immunotherapy through PD-L1 deglycosylation and CD47 inhibition. The photosensitizer protoporphyrin IX (PpIX) is conjugated to a PD-L1 deglycosylation peptide via a hydrophilic PEG linker, yielding the chimeric peptide Fmoc-K(PpIX)-PEG-GFTATPPAPDSPQEP. This chimeric peptide could self-assemble into nanomicelles capable of encapsulating the CD47 inhibitor RRx-001, generating the multifunctional photodynamic immunostimulant aGlyR. In vitro and in vivo results indicate that the photodynamic therapy (PDT) of aGlyR could disrupt breast cancer cells and trigger immunogenic cell death (ICD), leading to the release of tumor-associated antigens (TAAs) and the activation of immunological cascades. Additionally, the chimeric peptide component of aGlyR results in the deglycosylation and degradation of PD-L1, which restores T cell-mediated immune activity. Concurrently, the release of RRx-001 blocks the CD47 pathway, disrupting the antiphagocytic signaling of breast cancer cells and activating innate immune responses. This synergistic immunomodulatory approach effectively reverses the complex immunosuppressive factors, significantly enhancing the immunotherapeutic effects of conventional treatments.