A research group led by Prof. LI Yang at the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences has successfully developed a hypoxia-responsive nanogel (NG) for the delivery and penetration of diacerein (Dia) and (-)-epigallocatechin gallate (EGCG) into tumors, enhancing anti-tumor combinational immunotherapy by regulating the tumor inflammatory environment. 

The study was published in Advanced Healthcare Materials on Dec. 7, 2023. 

Tumor-infiltrating immune cells produce a range of pro-inflammatory cytokines and create an immunosuppressive tumor microenvironment (TME) by increasing the expression of PD-L1 and other pathways. This results in the reduction of functional T lymphocytes and facilitates tumor development, thereby limiting the effectiveness of immuno-oncology in clinical settings. 

To address this issue, the researchers proposed a synergistic strategy that can effectively improve the inflammatory TME and increase the tumor infiltration of cytotoxic T lymphocytes (CTLs). 

The proposed co-delivery system (denoted as D&E@NG) was constructed by linking Dia-PEG on the outer surface of NG via an azo bond, while loading EGCG within the cavity of NGs. 

The researchers found that after systemic administration in mice, when the particles reached the tumor site, the azo bond breakage released Dia under the hypoxia environment of the tumor, effectively alleviating the inflammatory TME, consequently inhibiting the infiltration of immunosuppressive cells (MDSCs and Tregs) and increasing the infiltration of CTLs in tumors. Further, it also induced tumor cell apoptosis effectively through the inhibition of the IL-6/STAT3 pathway. 

Additionally, after releasing Dia, the surface potential of these particles turned positive, making it easier to be taken up by tumor cells. In this scenario, the internalized EGCG could effectively decrease the expression of PD-L1 in tumors, restoring the killing ability of CTLs. 

In combination with TIM-3 blockade, a synergistic strategy that inhibits tumor growth and enhances CTLs infiltration and response could be finally achieved. 

"Our work provides a new approach for future research on eliciting effective antitumor immunity by suppressing adverse tumor inflammation," said Prof. LI. 

The anti-tumor immune mechanism of hypoxia-responsive nanogels. (Image by SIAT)

Media Contact:
ZHANG Xiaomin
Email:xm.zhang@siat.ac.cn