Inhibition of Immunosuppressive Tumors by Polymer-Assisted Inductions of Immunogenic Cell Death and Multivalent PD-L1 Crosslinking

Checkpoint blockade immunotherapies harness the host's own immune system to fight cancer, but only work against tumors infiltrated by swarms of preexisting T cells. Unfortunately, most cancers to date are immune-deserted. Here, a polymer-assisted combination of immunogenic chemotherapy and PD-L1 degradation is reported for efficacious treatment in originally nonimmunogenic cancer. Priming tumors with backbone-degradable polymer-epirubicin conjugates elicits immunogenic cell death and fosters tumor-specific CD8+ T cell response. Sequential treatment with a multivalent polymer-peptide antagonist to PD-L1 overcomes adaptive PD-L1 enrichment following chemotherapy, biases the recycling of PD-L1 to lysosome degradation via surface receptor crosslinking, and produces prolonged elimination of PD-L1 rather than the transient blocking afforded by standard anti-PD-L1 antibodies. Together, these findings establish the polymer-facilitated tumor targeting of immunogenic drugs and surface crosslinking of PD-L1 as a potential new therapeutic strategy to propagate long-term antitumor immunity, which might broaden the application of immunotherapy to immunosuppressive cancers.