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

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.image

Automated summary

This study proposes a dynamic immunomodulation strategy that addresses the limitations of systemic immune toxicity and tolerance in TLR7/8a therapy. It involves the use of prodrug-like TLR7/8a to control its activity and nanoliposomes for sustained release. The strategy activates innate immune cells and antigen-specific T cell responses, reprogramming immunosuppressive cells and reducing adverse effects. The results suggest the potential of this strategy for safe and effective cancer immunotherapy.