Self‐Accelerated Nanoregulators for Positive Feedback Ferroptosis‐Immunotherapy

Abstract Activating specific immunity through intelligent delivery of chemotherapeutic drugs shows great potential for effective tumor therapy. However, conventional tumor microenvironment‐responsive nanomedicines are often difficult to achieve both specificity and sensitivity, leading to severe adverse effects or limited drug release efficiency. Furthermore, the immunosuppressive microenvironment of tumor will also seriously restrict the treatment efficacy. In this work, a cascade‐responsive multi‐polyprodrug nanoregulator is developed. Under the tumor microenvironment with high hydrogen peroxide level, the nanoregulators can simultaneously release chemotherapeutic drugs (doxorubicin), indoleamine 2,3‐dioxygenase 1 inhibitor (1‐methyl‐tryptophan) and cinnamaldehyde in a self‐accelerating manner. The combination of reactive oxygen species‐induced ferroptosis and doxorubicin‐induced apoptosis can synergistically enhance immunogenic cell death and activate the immune response. The released1‐methyl‐tryptophan can promote cytotoxic T lymphocyte activation and reduce immune escape by inhibiting the tryptophan conversion. Meanwhile, it also enhances ferroptosis by inhibiting reactive oxygen species scavenging and cystine/glutamate antiporter expression, achieving the positive feedback ferroptosis‐immunotherapy. This work provides a self‐accelerated drug delivery strategy and a potential cooperation mode for tumor synergistic immunotherapy based on ferroptosis‐apoptosis.