Molecular Masking of Synthetic Immunomodulator Evokes Antitumor Immunity With Reduced Immune Tolerance and Systemic Toxicity by Temporal Activity Recovery and Sustained Stimulation

• Published in: Advanced materials (Weinheim) Vol. 36; no. 9; pp. e2309039 - n/a
• Main Authors: Shin, Hong Sik, Kim, Sohyun, Jin, Seung Mo, Yoo, Yeon Jeong, Heo, Jang Hun, Lim, Yong Taik
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.03.2024
• Subjects: Active control; Anticancer properties; Antigens; Cancer; cancer immunotherapy; Controlled release; Doxorubicin; immune checkpoint inhibitors; immune stimulation; Immune system; immune tolerance; Immunity; Immunomodulators; Immunosuppression; Immunotherapy; Lymphocytes; Masking; Recovery; Synergistic effect; toll‐like receptor agonist; Toxicity; immunosuppression; immune tolerance; immune stimulation; immune checkpoint inhibitors; cancer immunotherapy; toll-like receptor agonist
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.202309039

Activation 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. The clinical application of toll‐like receptor agonist (TLR7/8a) therapy is limited by systemic immune‐associated toxicity and immune tolerance. To address these limitations, a dynamic immunomodulation strategy incorporating masking and temporal activity recovery of TLR7/8a through prodrug‐like TLR7/8a (pro‐TLR7/8a) at the molecular level and a sustained release of active TLR7/8a from nanoliposomes (pro‐TLR7/8a) in a macroscale depot is designed.