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.
Adapting the mechanical strength between the implant materials and the brain tissue is crucial for the postoperative treatment of glioblastoma. However, no related study has been reported. Herein, we report an injectable lipoic acid‑iron (LA-Fe) hydrogel (LFH) that can adapt to the mechanical strength of various brain tissues, including human brain tissue, by coordinating Fe 3+ into a hybrid hydrogel of LA and its sodium salt (LANa). When LFH, which matches the mechanical properties of mouse brain tissue (337 ± 8.06 Pa), was injected into the brain resection cavity, the water content of the brain tissue was maintained at a normal level (77%). Similarly, LFH did not induce the activation or hypertrophy of glial astrocytes, effectively preventing brain edema and scar hyperplasia. Notably, LFH spontaneously degrades in the interstitial fluid, releasing LA and Fe 3+ into tumor cells. The redox couples LA/DHLA (dihydrolipoic acid, reduction form of LA in cells) and Fe 3+ /Fe 2+ would regenerate each other to continuously provide ROS to induce ferroptosis and activate immunogenic cell death. As loaded the anti-PDL1, anti-PDL1@LFH further enhanced the efficacy of tumor-immunotherapy and promoted tumor ferroptosis. The injectable hydrogel that adapted the mechanical strength of tissues shed a new light for the tumor postoperative treatment.
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