Recent advances in tumor-activated prodrug nanoparticles for cancer immunotherapy

Numerous therapeutic agents have been demonstrated to initiate antitumor immune responses, thereby driving significant progress in cancer immunotherapy. However, clinical translation is severely limited by persistent challenges, including systemic toxicity, the immunosuppressive tumor microenvironment (TME), and low nanoparticle delivery efficiency. Tumor-activated prodrug nanoparticles (PDNPs) integrate prodrug chemistry with nanoscale delivery, enabling localized drug activation in response to tumor microenvironmental cues or exogenous stimuli. Therapeutic specificity is improved and off-target toxicity is mitigated by this strategy, providing a promising platform for safe and effective drug delivery. Consequently, these systems have attracted extensive research attention. In this review, the design strategies, release mechanisms, and immunotherapeutic applications of TME-responsive and exogenous stimulus-responsive PDNPs are systematically detailed, together with active-targeting and hybrid strategies that further improve tumor-selective delivery and activation. Beyond serving as delivery vehicles for immunomodulators, these PDNPs are utilized in synergy with chemotherapy, photothermal/photodynamic therapy, and sonodynamic therapy to trigger immunogenic cell death. Furthermore, dendritic cell maturation and T-cell infiltration are promoted, thereby remodeling the immune microenvironment, particularly when administered in combination with immune checkpoint inhibitors. Finally, the key challenges and considerations for the clinical translation of tumor-activated PDNPs are highlighted, with the aim of guiding further research progress.