Affiliation:
1. SKKU Advanced Institute of Nanotechnology (SAINT) Department of Nano Science and Technology Department of Nano Engineering School of Chemical Engineering Sungkyunkwan University (SKKU) 2066 Seobu‐ro, Jangan‐gu Suwon Gyeonggi‐do 16419 Republic of Korea
Abstract
AbstractActivation of the innate immune system counteracts tumor‐induced immunosuppression. Hence, small molecule‐based toll‐like receptor 7/8 agonists (TLR7/8a), which can modulate immunosuppression in the tumor microenvironment along with the activation of innate immunity, are emerging as essential components of cancer immunotherapy. However, the clinical application of synthetic TLR7/8a therapies is limited by systemic immune‐associated toxicity and immune tolerance induced by uncontrolled stimulatory activities and repeated treatments. To address these limitations, a dynamic immunomodulation strategy incorporating masking and temporal recovery of the activity of TLR7/8a through prodrug‐like TLR7/8a (pro‐TLR7/8a) at the molecular level and a sustained and controlled release of active TLR7/8a from nanoliposome (pro‐TLR7/8a) (NL(pro‐TLR7/8)) in a macroscale depot are designed. Immunization with cationic NL(pro‐TLR7/8) and anionic antigens triggers robust activation of innate immune cells as well as antigen‐specific T cell responses, eliciting reprogramming of immunosuppressive cells into tumor‐suppressive cells, with decreased systemic adverse effects and immune tolerance. Combination treatment with NL(pro‐TLR7/8a) and immune checkpoint inhibitors (anti‐CTLA‐4 plus anti‐PD‐L1) or nanoliposomes (Doxorubicin) has synergistic effects on antitumor immunity in various tumor models. The concept of pro‐TLR7/8a suggested herein may facilitate the advancement of small‐molecule‐based immunomodulators for clinical translation and safe and effective cancer immunotherapy.
Funder
National Research Foundation of Korea
Subject
Mechanical Engineering,Mechanics of Materials,General Materials Science