LAUSR

Here, a protein farnesyltransferase (PFTase)-driven plasma membrane (PM)-targeted chimeric peptide PpIX-C6-PEG8-KKKKKKSKTKC-OMe (PCPK) was designed for PM-targeted photodynamic therapy (PM-PDT) and enhanced immunotherapy via tumor cell PM damage and fast release of damage-associated molecular patterns (DAMPs). The PM targeting ability of PCPK is originated from cellular K-Ras signaling, which occurs exclusively for driving the corresponding proteins to PM by PFTase. With the conjugation of photosensitizer protoporphyrin IX (PpIX), PCPK could generate cytotoxic reactive oxygen species (ROS) to deactivate membrane-associated proteins, initiate lipid peroxidation and destroy PM with an extremely low concentration (1 μM) under light irradiation. The specific PM damage further induced the fast release of DAMPs (high-mobility group box 1 and ATP), resulting in stronger antitumor immune responses than that of conventional cytoplasm-localized PDT. This immune-stimulating PM-PDT strategy also exhibited the inhibition of distant metastatic tumors when combined with programmed cell death receptor 1 blockade therapy.