Plasma Membrane Targeted Photodynamic Nanoagonist to Potentiate Immune Checkpoint Blockade Therapy by Initiating Tumor Cell Pyroptosis and Depleting Infiltrating B Cells

Abstract Immune checkpoint blockade (ICB) therapy has achieved remarkable benefits in the treatment of malignant tumors, but the clinical response rates are unsatisfied due to the low tumor immunogenicity and the abundant immunosuppressive cells. Herein, a plasma membrane targeted photodynamic nanoagonist (designated as PMTPN) is developed to potentiate ICB therapy by initiating tumor cell pyroptosis and depleting infiltrating B cells. PMTPN is composed of a rationally designed chimeric peptide sequence loaded with Bruton's tyrosine kinase inhibitor (Ibrutinib). Notably, PMTPN is capable of sequentially targeting tumor and tumor cell membrane to trigger immunogenic pyroptosis and cause overwhelming release of cytokines, promoting dendritic cells maturation, and cytotoxic T lymphocytes (CTLs) activation. Meanwhile, PMTPN can also deplete infiltrating B cells and reduce the secretion of interleukin‐10 to decrease immunosuppressive regulatory T cells and enhance CTLs infiltration. Beneficially, the synergistic immune modulating characteristics of PMTPN potentiate ICB therapy to simultaneously eliminate primary and distant tumors. This study offers a promising strategy to elevate the immunotherapeutic response rate in consideration of the complex immunosuppressive factors.