NLRP3 promotes NK cell-mediated cytotoxicity and inhibits colorectal cancer development via the NKG2D signaling pathway

Colorectal cancer progression involves tumor metastasis and immune evasion, with the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome and Natural Killer Group 2D (NKG2D) signaling pathway playing key roles. Their relationship in regulating NK cell-mediated cytotoxicity and CRC progression remains unclear. This study investigates NLRP3’s modulation on tumor dynamics and NK cell responses to uncover new therapeutic targets. Colon cancer situ models were used to analyze tumor development after NLRP3 overexpression (oeNLRP3) and the effects of NK-92 cells with silencing NKG2D using TUNEL, immunohistochemistry staining, flow cytometry, and molecular assays. Also, a co-culture model of HCT116 and NK-92 cells was used. Focus was on tumor metastasis, apoptosis, NK cell-mediated cytotoxicity, NLRP3 and NKG2D pathways. OeNLRP3 increased apoptosis, inhibited tumor growth and enhanced immune markers. NK cells with silencing NKG2D reversed these benefits, emphasizing the importance of the NLRP3-NKG2D axis. In HCT116 cells, oeNLRP3 boosted NK cell-mediated cytotoxicity, and apoptosis, and decreased cell migration and invasion. Elevated pro-inflammatory and pro-apoptotic protein levels indicated activated immune and apoptotic pathways. NKG2D silencing mitigated these effects. NLRP3 inhibition of tumor metastasis and apoptosis promotion in colon cancer through NKG2D modulation offers a potential therapeutic avenue. The NLRP3-NKG2D axis is critical for colorectal cancer management. These results suggest a promising target for treatment strategies and providing insights into the inflammasome’s role in cancer biology. Further preclinical and clinical investigations are needed to evaluate the translational potential of this axis in developing more effective approaches for colorectal cancer management.