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

Author:

Luo Wenhe12,Zeng Yanqiao12,Song Qingle12,Wang Yu12,Yuan Feng12,Li Qi12,Liu Yingnan12,Li Su12,Jannatun Nahar12,Zhang Guofang12,Li Yang12ORCID

Affiliation:

1. Laboratory of Inflammation and Vaccines Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen Guangdong 518055 China

2. Laboratory of Immunology and Nanomedicine & China‐Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation Shenzhen Institute of Advanced Technology Chinese Academy of Sciences Shenzhen Guangdong 518055 China

Abstract

AbstractDespite 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, a TME hypoxia‐responsive nanogel (NG) is developed to enhance the delivery and penetration of diacerein and (‐)‐epigallocatechin gallate (EGCG) in tumors. After systemic administration, diacerein effectively improves the tumor immunosuppressive condition through a reduction of MDSCs and Tregs in TME, and induces tumor cell apoptosis via the inhibition of IL‐6/STAT3 signal pathway, realizing a strong antitumor effect. Additionally, EGCG can effectively inhibit the expression of PD‐L1, restoring the tumor‐killing function of CTLs. The infiltration of CTLs increases at the tumor site with activation of systemic immunity after the combination of TIM3 blockade therapy, ultimately resulting in a strong antitumor immune response. This study provides valuable insights for future research on eliciting effective antitumor 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.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Guangdong Province

Instituto Nacional de Ciência e Tecnologia Centro de Estudos das Adaptações da Biota Aquática da Amazônia

Publisher

Wiley

Subject

Pharmaceutical Science,Biomedical Engineering,Biomaterials

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