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.
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Data availability
The raw sequencing data reported in this study have been deposited in the Genome Sequence Archive (GSA) at the National Genomics Data Center (NGDC), China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (accession No. PRJCA036988) and are publicly accessible at https://ngdc.cncb.ac.cn/gsa. The scRNA-seq data for IR-resistant IR-MC38 and IR-sensitive MC38 tumors, as well as the RNA-seq data for IR-resistant IR-MC38 and IR-sensitive MC38 cells, have been deposited in the NGDC database (accession nos. CRA023580 and CRA023695, respectively). Additionally, the data on NEK8-binding proteins identified by IP/MS in MC38 and CT26 cells, the in vitro kinase assay data screening NEK8 phosphorylation sites on LDHA, the CUT&Tag data for H3K8la in MC38-shNek8 and MC38-shNC cells, and the RNA-seq data for shNC_IR and shNek8_IR tumors are available in the NGDC database under accession nos. OMIX009338,OMIX009336(https://ngdc.cncb.ac.cn/omix/release/OMIX009336), CRA023632, and CRA023578, respectively. This paper does not report the original code. All the other data supporting the findings of this study are available within the article and its Supplementary Information files. Source data are provided as a Source Data file. Source data are provided with this paper.
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Acknowledgements
This work was supported by grants from the Chongqing Technology Innovation and Application Development Special Major Project (CSTB2024TIAD-STX0003 to L.L.), the National Natural Science Foundation of China (Grant Nos. 82273358 to L.L.and 81872041 to L.L.), the Open Project of the Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China (No. 2024jsz1006 to M.Z.L.), the President Foundation of Nanfang Hospital, Southern Medical University (Grant Nos. 2025B026 to M.Z.L. and 2025B034 to J.F.Q.) and the Scientific and Technological Innovation Cultivation of College Students in Guangdong Province (Climbing Program) (pdjh2026bk049 to J.Q.W).
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M.Z.L. conceived and designed the study. M.Z.L.,Y.F.N., J.Q.W., Y.N.C, J.F.Q, Y.F.L., H.Y.C, L.W, F.F.W, H.X.Z, F.Y.H, J.H.H, Z.L.C and B.Y.X performed the experiments and analyzed the data. X.Z. conducted the bioinformatics analysis. M.Z.L. and Y.F.N. wrote the first draft of the manuscript. M.Z.L., Y.F.N., and J.Q.W. edited the manuscript,The corresponding author L.L. coordinated the overall organization, design, and writing of the article. All other authors contributed equally to the conception of the study, literature review, and editing of the manuscript and figures. All authors approved the final version of the manuscript.
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Li, M., Ni, Y., Wu, J. et al. NEK8 kinase-mediated lactate increase impairs antitumor immunity decreasing radiotherapy sensitivity in colorectal cancer. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70657-z
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DOI: https://doi.org/10.1038/s41467-026-70657-z
