A nanotherapeutic strategy to reverse NK cell exhaustion

Shuojiong Pan, Jun Guan, Banruo Xianyu, Yizheng Tan, Tianyu Li, and Huaping Xu

Adv. Mater.; 2023, 23, 2211370.

As a specialized immune effector cell, natural killer (NK) cells play a very important role in immunotherapy, but tumor immunosuppression caused by abnormal expression of cancer cells seriously weakens its therapeutic effect and leads to exhaustion. Here, we developed a self-assembled selenium containing nanoparticles (NPs) composed of Cetuximab, C5SeSeC5 and inhibitor LY345899 to reverse NK cell exhaustion. The obtained NPs can target EGFR on the surface of cancer cells and locate in mitochondria. The released LY345899 could inhibit the activity of methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) and produce excessive reactive oxygen species (ROS), leading to the formation of seleninic acid, further reducing the expression of HLA-E, which was responsible for the NKG2A-related NK cell inhibition. As a result, the enhanced NK cell-mediated immunotherapy in conjunction with the Cetuximab-mediated ADCC effect can not only effectively inhibit the growth of xenograft tumors, but also significantly suppress the growth of untreated distant tumors via the abscopal effect. This work, the combination of seleninic acid, LY345899 and Cetuximab, provides a new strategy for reversing NK cell exhaustion and has great potential for use in the treatment of metastatic tumors.