A <scp>GSH</scp>‐Responsive Immune‐Stimulating Polypeptide Hydrogel Loaded with Chemotherapeutics, <scp>IDO</scp> Inhibitor and Immune Checkpoint Blocking Antibody for Enhanced Anti‐Tumor Chemo‐Immunotherapy

Comprehensive Summary Due to the immunosuppressive tumor microenvironment (TME), T cells are usually inactivated and tend to differentiate into regulatory T cells (Tregs) in the tumor tissues, which seriously hinders the anti‐tumor efficiency of immunotherapy. In this study, an immune‐stimulating polypeptide hydrogel conjugated with an indoleamine‐2,3‐dioxygenase (IDO) inhibitor, 1‐methyl‐ D ‐tryptophan (D1MT), through a glutathione (GSH)‐responsive spacer was developed as an immunotherapy platform capable of regulating the TME. A combined immunotherapy system was further constructed through encapsulating doxorubicin (Dox) and immune checkpoint blocking antibody targeting programmed cell death protein 1 (aPD‐1) in the hydrogel. Dox released from the hydrogel could cause the immunogenic cell death (ICD) of tumor cells and induce the maturation of antigen presenting cells (APCs). After intratumoral injection, the multiple agent‐loaded hydrogel elicited effective anti‐tumor immunity in mice bearing B16F10 melanoma. Moreover, compared with the control hydrogel without D1MT, the immune‐stimulating hydrogel showed better efficiency in improving the immunosuppressive TME with increased number of activated T cells and reduced number of Tregs. Therefore, the immune‐stimulating hydrogel has great potential as a stimuli‐responsive platform for regulating suppressive TME and enhanced anti‐tumor chemo‐immunotherapy.