先天免疫系统的激活可以抵消肿瘤引起的免疫抑制。因此，基于小分子的 Toll 样受体 7/8 激动剂 (TLR7/8a) 可以调节肿瘤微环境中的免疫抑制并激活先天免疫，正在成为癌症免疫治疗的重要组成部分。然而，合成TLR7/8a疗法的临床应用受到系统免疫相关毒性和不受控制的刺激活动和重复治疗引起的免疫耐受的限制。为了解决这些局限性，动态免疫调节策略结合了分子水平上的前药样 TLR7/8a (pro-TLR7/8a) 掩蔽和暂时恢复 TLR7/8a 的活性，以及​​活性 TLR7/8a 的持续和受控释放设计了来自纳米脂质体 (pro-TLR7/8a) (NL(pro-TLR7/8)) 的宏观储存库。使用阳离子 NL(pro-TLR7/8) 和阴离子抗原进行免疫，引发先天免疫细胞的强烈激活以及抗原特异性 T 细胞反应，引发免疫抑制细胞（M2 巨噬细胞和 MDSC）重新编程为肿瘤抑制细胞（M1 巨噬细胞） ），降低全身不良反应和免疫耐受。 NL（pro-TLR7/8a）与免疫检查点抑制剂（抗CTLA-4加抗PD-L1）或纳米脂质体（Dox）联合治疗对多种肿瘤模型的抗肿瘤免疫具有协同作用。本文提出的pro-TLR7/8a的概念可能有助于促进基于小分子的免疫调节剂的临床转化和安全有效的癌症免疫治疗的进展。本文受版权保护。保留所有权利。本文受版权保护。版权所有。

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 has been 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 were designed. Immunization with cationic NL(pro-TLR7/8) and anionic antigens triggered robust activation of innate immune cells as well as antigen-specific T cell responses, eliciting reprogramming of immunosuppressive cells (M2 macrophages and MDSCs) into tumor-suppressive cells (M1 macrophages), 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 (Dox) had 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. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.