Recent Advances in Prodrug-Loaded Nanoparticles for Enhanced Immunotherapy Efficacy.

Immunotherapy has emerged as an important approach for cancer treatment. However, most drugs for activating the cancer-immunity cycle have serious side effects from systemic off-target action, endangering patients' safety. Prodrug-loaded nanoparticles integrate prodrug activation strategies based on passive or active targeted delivery, which is expected to improve the enrichment of drugs in tumors, reduce the activation of drugs in normal tissues, and enhance the drugs' tumor selectivity. For example, adjuvants represented by Toll-like receptor 7/8 (TLR7/8) agonists and stimulator of interferon genes (STING) agonists are promising for the de novo priming of antitumor immunity. However, these drugs face pressing challenges in achieving tumor-specific immune activation to enhance the therapeutic effect and minimize systemic toxicity. This review systematically analyzes recent advances in these prodrug-loaded nanoparticles for precise controlled release adjuvants in tumors, focusing on TLR7/8 and STING agonists. We discuss the tumor microenvironment-driven prodrug activation, externally triggered prodrug activation, and explore the generalized design principles and mechanisms applicable to prodrug-loaded nanoparticles. Furthermore, we explore these adjuvants' current status, challenges, and future development direction in the clinical translation. This article aims to inspire the further development of these agonists. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.