Self‐Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8⁺ T Cells

Abstract Intratumoral CD8⁺ T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T‐cell‐mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects of these old drugs has not been realized. The self‐degradable PMI nanogels carrying two repurposed immune modulators, imiquimod (Imi) and metformin (Met), are reported for TME‐responsive drug release. It remodels the TME through the following aspects: 1) promoting dendritic cells maturation, 2) repolarizing M2‐like tumor‐associated macrophages, and 3) downregulating PD‐L1 expression. Ultimately, PMI nanogels reshaped the immunosuppressive TME and efficiently promote CD8⁺ T cell infiltration and activation. These results support that PMI nanogels can potentially be an effective combination drug for enhancing the antitumor immune response of anti‐PD‐1 antibodies.