Oncolytic Hydrogel Enhances Immune Checkpoint Blockade by Generating In Situ Vaccine, Remodeling Tumor Physical and Metabolic Barriers

Abstract

Although traditional immunogenic cell death (ICD) inducers generate in situ vaccines (ISV) to potentiate antiprogrammed cell death ligand 1 (anti-PDL1) antibodies therapy, their efficacy remains limited. This limitation may be attributed to the physical barrier created by extracellular matrix (ECM) and immunosuppressive metabolic barrier mediated by adenosine. Here, we report an oncolytic polymer (OP), a well-designed ε-polylysine derivative with ICD-inducing capacity, which can simultaneously facilitate the release of endogenous ECM-degrading enzyme, Cathepsin B. The OP alone is sufficient to induce ISV within tumors and disrupt physical barriers without the need for any additional ECM-regulatory drugs. Furthermore, an oncolytic hydrogel codelivering OP and CD73 inhibitor (AMPCP) was developed (OP@AMPCP Gel). Intratumoral injection of OP@AMPCP Gel generates ISV, decreases tumor ECM deposition, enhances antigen delivery to lymph nodes, increases immune cell infiltration, and promotes penetration of anti-PDL1 antibodies, while reducing adenosine levels. OP@AMPCP Gel+anti-PDL1 treatment showed better therapeutic efficacy than oxaliplatin + anti-PDL1 group against breast cancer. Moreover, 80% of melanoma-bearing mice showed complete tumor regressions after receiving OP@AMPCP Gel + anti-PDL1 treatment. Impressively, OP@AMPCP Gel + anti-PDL1-treated mice showed resistance to tumor rechallenge and metastasis, suggesting induction of long-lasting systemic antitumor immunity. Overall, this study presents an oncolytic hydrogel capable of inducing ISV and remodeling the tumor physical barrier and immunosuppressive barrier, offering a promising strategy for customizing personalized immunotherapy.