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

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-1/PD-L1, CTLA-4, LAG-3, IDO, and the CD47/CD24 axis. The mechanisms of action of these prodrugs are detailed, highlighting how they can be activated in the tumor microenvironment to exert their therapeutic effects. Additionally, the review discusses issues related to ICIs drug stability and controlled release, as well as the challenges and prospects in this field. Despite the challenges in prodrug design, innovative nanotechnologies and combination therapeutic strategies hold promise for more effective cancer immunotherapy.