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

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.

Automated summary

Intratumoral CD8(+) T cells play a crucial role in cancer immunotherapy, but the immunosuppressive tumor microenvironment (TME) limits their function and infiltration. Drug repurposing has identified existing drugs as immune modulators to improve TME immunosuppression and reactivate T-cell-mediated antitumor immunity. However, the suboptimal availability of these drugs in tumors hampers their full immunomodulatory potential. Self-degradable PMI nanogels carrying repurposed immune modulators (imiquimod and metformin) are developed for TME-responsive drug release. They remodel the TME by promoting dendritic cell maturation, repolarizing M2-like tumor-associated macrophages, and downregulating PD-L1 expression. Ultimately, the PMI nanogels reshape the immunosuppressive TME and efficiently enhance CD8(+) T cell infiltration and activation. These results suggest that PMI nanogels could be an effective combination drug with anti-PD-1 antibodies to enhance antitumor immune responses.