Hyunchul Jung^1,10, Hong Sook Kim^2,10, Jeong Yeon Kim¹, Jong-Mu Sun², Jin Seok Ahn², Myung-Ju Ahn², Keunchil Park², Manel Esteller^3,4,5,6,7, Se-Hoon Lee^2,8,* & Jung Kyoon Choi^1,9,*

¹ Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Republic of Korea.
² Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea.
³ Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet, Barcelona, Catalonia, Spain.
⁴ Centro de Investigacion Biomedica en Red Cancer (CIBERONC), 28029 Madrid, Spain.
⁵ Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
⁶ Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain.
⁷ Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
⁸ Department of Health Sciences and Technology, Samsung Advanced Institute of Health Science and Technology, Sungkyunkwan University, Seoul 06351, Republic of Korea.
⁹ Penta Medix Co., Ltd., Seongnam-si, Gyeongi-do 13449, Republic of Korea.
¹⁰ These authors contributed equally: Hyunchul Jung, Hong Sook Kim.

^*Correspondence and requests for materials should be addressed to S.-H.L. or to J.K.C.

Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy.