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

Abstract

AbstractAlthough 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.