Chemotherapy-induced senescent nasopharyngeal carcinoma cells suppress NK cell-mediated antitumor immunity by upregulating EBI3 via mtDNA-cGAS-STING pathway.

Chemotherapy is one of the important means to improve the 5-year survival rate of nasopharyngeal carcinoma (NPC) patients, and commonly used chemotherapy drugs include cisplatin and gemcitabine. Previous studies have shown that chemotherapy can induce some tumor cells to exhibit a senescent phenotype, thereby altering the tumor microenvironment towards tumor immune suppression and tumor recurrence. However, the role and detailed mechanism of chemotherapy in the senescence of NPC cells are not yet clear, and further in-depth research is needed. This study focuses on the mechanism of cisplatin-induced cellular senescence, a major form of chemotherapy-induced senescence, in the progression of NPC. Our study found that cisplatin induces tumor cell senescence, upregulates EBI3 expression, and promotes abnormal secretion of IL-35 to mediate tumor immune escape. Specifically, senescent NPC cells release mtDNA due to mitochondrial damage, which in turn activates the cGAS-STING signaling pathway. Activation of this pathway induces the nuclear translocation of NF-κB p65, which directly binds to the EBI3 promoter and significantly upregulates EBI3 expression. Subsequently, EBI3 binds to the p35 subunit to form IL-35, which activates the JAK-STAT1 pathway of NK cells through IL-12Rβ2/GP130 receptors, inducing upregulation of the inhibitory receptor NKG2A and thereby weakening the anti-tumor function of NK cells. This study reveals for the first time a novel molecular mechanism by which cisplatin-induced senescent cells, a representative of chemotherapy-induced senescent cells, regulate NK cell anti-tumor function through the EBI3/IL-35 axis, and identifies EBI3 as a key molecular target involved in chemotherapy-induced senescence-mediated immune suppression in NPC, providing important experimental evidence for developing targeted immunotherapy strategies for NPC.