A research group led by Prof. LI Yang at the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences has developed a hypoxia-responsive nanogel (NG) for the delivery and penetration of diacerein (Dia) and (-)-epigallocatechin gallate (EGCG) into tumors, thereby modulating the tumor inflammatory environment and bolstering anti-tumor combinational immunotherapy. The study was published in Advanced Healthcare Materials. 

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

After releasing Dia, the surface charge of these particles turned positive, making it easier to be taken up by tumor cells. Consequently, the internalized EGCG could effectively reduce the expression of PD-L1 in tumors, restoring the killing ability of CTLs.