Abstract
Toll-like receptor 7/8 (TLR7/8) agonists (such as resiquimod-R848) are potent immune adjuvants. However, their clinical use is limited by severe systemic toxicity. To address this challenge, prodrug strategies have emerged as a key solution. In recent years, researchers have developed various prodrugs through chemical modifications. These prodrugs can be selectively activated within the tumor microenvironment in response to specific triggers, such as hypoxia, ultrasound, radiotherapy, or overexpressed enzymes. This approach enables spatiotemporally controlled release of the active drug and significantly reduces systemic inflammatory responses. To further enhance therapeutic efficacy and targeting precision, advanced delivery systems (protein nanoparticles, polymeric nanogels, liposomes, and nanoparticle suspensions) have been employed to carry these prodrugs. Such systems not only provide sustained release but also allow co-delivery of antigens, siRNA, or chemotherapeutic agents. This facilitates synergistic modulation of the tumor immune microenvironment. When combined with immune checkpoint inhibitors (ICIs) or chemotherapy, they exhibit strong synergistic antitumor effects and induce durable immune memory. Notably, several of these approaches have already entered clinical evaluation. By summarizing recent advances in both prodrug chemistry and sophisticated delivery platforms, this review highlights a promising path toward precise and controllable delivery of TLR7/8 agonists. We hope this integrated strategy will pave the way for safer and more effective cancer immunotherapies.