MICA/B-driven NK cell dysfunction promotes cervical cancer via Toll signaling

Abstract

The immune status is of crucial importance in the development of cervical cancer (CC). MICA/B, as a major histocompatibility complex Class I associated protein, mediates anti-tumor immunity by activating NK cell receptors. However, the precise mechanisms underlying MICA/B-mediated regulation of CC progression remain poorly understood. This study combined spatial transcriptome sequencing and bioinformatics analysis and found that MICA/B was significantly highly expressed in CC tissues and cells, accompanied by more NK cell infiltration. Flow cytometry and Cell Functional assays, Knockdown of MICA/MICB weakens the activation receptor efficacy of NK cells, enhances the inhibitory signal, leads to a decrease in cytotoxicity, and simultaneously upregulates Cyclin expression in CC cells while downregulating BCL-2/BAX. Tumor xenograft models indicated that tumors with MICA knockdown exhibited a growth tendency in the presence of natural killer (NK) cells. Mechanistically, MICA/B regulates inflammatory factors such as IL-6 and CXCL10/11 through the Toll-like signaling pathway, affecting the function of NK cells. Thus, MICA/B expression on cervical cancer cells plays a pivotal role in eliciting NK cell-mediated antitumor immunity. Their downregulation attenuates NK cell function, promoting cervical cancer cell proliferation and survival via the Toll signaling pathway. These findings highlight the potential of targeting MICA/B-NK cell interactions as a therapeutic strategy for cervical cancer.