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

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. Radiotherapy response in colorectal cancer (CRC) is often limited and recurrence is common. Here, the authors show that the kinase NEK8 induces radioresistance by lactate-mediated immunosuppression and that inhibiting NEK8 restores antitumor immunity and improves radiotherapy sensitivity in preclinical CRC.