Self-driven nanoprodrug platform with enhanced ferroptosis for synergistic photothermal-IDO immunotherapy

Insufficient immune stimulation and stubborn immune resistance are the critical factors limiting tumor immu-notherapy. Here, we report a multifunctional nanoprodrug platform with self-driven indoximod (IND) release and oxidative stress amplification. The aim is to awaken immune responses and block the indoleamine 2,3-diox-ygenase (IDO) pathway through a combination of ferroptosis, photothermal therapy, and immunotherapy. This nanosystem improved the delivery efficiency of IND due to click chemistry linked ROS responsive prodrug and self-driven drug release. Meanwhile, the tactic of simultaneously increasing ROS and eliminating GSH amplified oxidative stress and strengthened ferroptosis, which further enhanced immunogenicity along with polydopamine-based photothermal therapy. IDO immunization combined with ferroptosis as well as photo -thermal therapy not only stimulated immune response, but also reversed immune suppression with enhanced immune memory. Therefore, primary tumor, distant tumor, and cancer metastasis were inhibited. This study provides a perspective on immunotherapeutics for cancer treatment.

Automated summary

We report a multifunctional nanoprodrug platform that combines ferroptosis, photothermal therapy, and immunotherapy to awaken immune responses and block the indoleamine 2,3-diox-ygenase (IDO) pathway, thereby overcoming the limitations of tumor immunotherapy. The platform improved the delivery efficiency of indoximod (IND) and strengthened immune response through the self-driven release of IND and the amplification of oxidative stress. This study provides a new perspective on immunotherapeutics for cancer treatment.