NEK8 kinase-mediated lactate increase impairs antitumor immunity decreasing radiotherapy sensitivity in colorectal cancer.

Abstract

Radiotherapy effectively treats colorectal cancer (CRC), but local recurrence remains common and abscopal effects-regression of tumors distant from irradiated sites-are rarely observed even with immune checkpoint inhibitors. Here we show that the protein kinase NEK8, highly expressed in CRC, promotes radioresistance by suppressing anti-tumor immunity. In radiation-resistant tumors, NEK8 phosphorylates lactate dehydrogenase A (LDHA), driving lactate overproduction. This metabolite promotes histone modifications that silence antigen presentation machinery, while extracellular lactate directly impairs CD8⁺ T cell function, collectively excluding CD8⁺ T cell from the tumor microenvironment. Pharmacological inhibition of NEK8 using CX6258 restores CD8⁺ T cell infiltration and enhances both local and systemic tumor control following radiotherapy. These findings establish NEK8 as a promising therapeutic target for overcoming radioresistance and inducing abscopal responses in CRC.