Hypomethylating agents(HMA) currently are widely used in the treatment of myelodysplastic syndromes (MDS), provide a significant improvement in the treatment of MDS. However, resistance to HMA is an almost universal phenomenon. This review was focused on immune effects related to DNA methylation, and to explore the mechanism underlying HMA resistance involved in immune checkpoint pathways. However, the optimal role of checkpoint blockade therapy (CBT) and immune checkpoint pathways remain in HMA failure questionable. The better understanding of immune checkpoint pathways in resistance of HMA offers a compelling rationale to introduce CBT in patients as a novel treatment option. CBT is an established strategy in solid tumors with potential as an adjunctive therapy in hematologic malignancies, therefore, may alter the treatment landscape in MDS. The suitability and effectiveness of combining HMA with CBT need to be confirmed by the results of ongoing clinical trials, so as to find novel strategies to improve outcome after failure of HMA.