Our in-depth methylation profiling identified the specific demethylation status of exhaustion markers, including PDCD1, HAVCR2, and LAYN. In addition, TF binding site analysis in HypoMRs for the enrichment of known TFs identified exhaustion-related TFs such as NR4A1, BATF, and EGR2. The current common epigenetic approaches for cancer treatment are the administration of demethylating agents such as azacitidine, which have a broad but undefined effect on the genome [39]. Here, NR4A1 is linked to cancer.