Strengthening the Combinational Immunotherapy from Modulating the Tumor Inflammatory Environment via Hypoxia-Responsive Nanogels.

Despite the success of immuno-oncology in clinical settings, the therapeutic efficacy is lower than the expectation due to the immunosuppressive inflammatory tumor microenvironment (TME) and the lack of functional lymphocytes caused by exhaustion. To enhance the efficacy of immuno-oncotherapy, a synergistic strategy should be used that can effectively improve the inflammatory TME and increase the tumor infiltration of cytotoxic T lymphocytes (CTLs). Herein, we developed a TME hypoxia-responsive nanogel (NG) to enhance the delivery and penetration of diacerein and (-)-epigallocatechin gallate (EGCG) in tumors. After systemic administration, diacerein effectively improved the tumor immunosuppressive condition through a reduction of MDSCs and Tregs in TME, and induced tumor cells apoptosis via the inhibition of IL-6/STAT3 signal pathway, realizing a strong anti-tumor effect. Additionally, EGCG could effectively inhibit the expression of PD-L1, restoring the tumor-killing function of CTLs. The infiltration of CTLs increased at the tumor site with activation of systemic immunity after the combination of TIM3 blockade therapy, ultimately resulting in a strong anti-tumor immune response. This study provides valuable insights for future research on eliciting effective anti-tumor immunity by suppressing adverse tumor inflammation. The feasible strategy proposed in this work may solve the urgent clinical concerns of the dissatisfactory checkpoint-based immuno-oncotherapy. This article is protected by copyright. All rights reserved.