Research progress and future perspectives of prodrug strategies for immune checkpoint inhibitors in cancer immunotherapy. (2025)

Immune checkpoint inhibitors (ICIs) have emerged as a major milestone in cancer immunotherapy. However, their clinical application is limited by significant inter-individual differences in efficacy, the development of resistance, and immune-related adverse events (irAEs). Prodrugs are specially designed to be activated within the tumor microenvironment and release their active components. The concept of prodrugs offers a novel approach to addressing these challenges. This targeted activation not only boosts the effectiveness of ICIs but also minimizes systemic toxicity. This review outlines the biological basis of immune checkpoints and the approved inhibitors targeting them. In addition, it presents the latest research on prodrug designs targeting various immune checkpoints, including PD-