Three-in-One Oncolytic Adenovirus System Initiates a Synergetic Photodynamic Immunotherapy in Immune-Suppressive Cholangiocarcinoma.

Although photodynamic immunotherapy has been promoted in the clinical practice of cholangiocarcinoma, the insensitivity to photodynamic immunotherapy remains to be a great problem. This can be largely attributed to an immune-suppressive tumor microenvironment (TME) manifested as immature myeloid cells and exhausted cytotoxic T lymphocytes. Here, a three-in-one oncolytic adenovirus system PEG-PEI-Adv-Catalase-KillerRed (p-Adv-CAT-KR) has been constructed to multiply, initiate, and enhance immune responses in photodynamic immunotherapy, using genetically-engineered KillerRed as photosensitizer, catalase as in situ oxygen-supplying mediator, and adenovirus as immunostimulatory bio-reproducible carrier. Meanwhile, PEG-PEI is applied to protect adenovirus from circulating immune attack. The administration of p-Adv-CAT-KR induces increased antigen presenting cells, elevated T cell infiltrations, and reduced tumor burden. Further investigation into underlying mechanism indicates that hypoxia inducible factor 1 subunit alpha (Hif-1α) and its downstream PD-1/PD-L1 pathway contribute to the transformation of immune-suppressive TME in cholangiocarcinoma. Collectively, the combination of KillerRed, catalase, and adenovirus brings about multi-amplified antitumor photo-immunity and has the potential to be an effective immunotherapeutic strategy for cholangiocarcinoma.