Carbon ion (12C6+) irradiation induces the expression of Klrk1 in lung cancer and optimizes the tumor microenvironment based on the NKG2D/NKG2D-Ls pathway.

Abstract With the identification of “negative immune regulation” defects in the immune system and the continuous improvement of immunotherapy, natural killer cells (NK) have received more attention, especially as tools in combined immunotherapy. Carbon ions (12C6+) have become the ideal radiation for combined immunotherapy due to their significant radiobiological advantages and synergistic effects. The purpose of this study was to explore the NK cell-mediated cytotoxicity pathway and related mechanisms in lung cancer induced by carbon ion irradiation. KLRK1, which specifically encodes the NKG2D receptor, was significantly correlated with the prognosis, clinical stage, functional status of NK cells, and the immune microenvironment of lung cancer, as shown by bioinformatics analysis. Based on RNA-seq data of Lewis lung cancer in C57BL/6 mice, carbon ion irradiation was found to significantly induce Klrk1 gene expression and activate the NKG2D/NKG2D-Ls pathway. The Treg inhibition pathway combined with carbon ion radiotherapy could significantly increase the infiltration and function of NK cells in the tumor microenvironment of lung cancer and prolong the survival time of C57BL/6 mice. In conclusion, carbon ions have significant radiobiological advantages, especially under conditions of combined immunotherapy. Carbon ions combined with Treg inhibitors can significantly improve the infiltration and functional status of NK cells.