Background: Immune-checkpoint blockade (ICB) is a recent addition to the treatment options for breast cancer, especially the triple-negative (TNBC) subset. Inhibiting immunosuppressive factors in the tumor microenvironment (TME) and preventing or reversing T cell exhaustion may increase the likelihood of a response to ICB. We have shown that decitabine and guadecitabine, DNA methyltransferase inhibitors (DNMTi), prevent the systemic and TME accumulation of myeloid-derived suppressor cells (MDSCs), which are immunosuppressive. Results: Here, we show that adding DNMTi to the neoadjuvant + adjuvant ICB-based treatment of ICB-resistant 4T1 and E0771 murine tumors in Balb/C and C57Bl/6 mice, respectively, effectively reduced the tumor burden, with 52% of 4T1 tumors completely regressing across several studies. DNMTi-based therapy overcame ICB resistance (ICBR) in a selected subline of E0771, and treated tumors showed a reduction in MDSCs. We also show that, in E0771, DNMTi can overcome ICBR to multiple checkpoint inhibitors, and in 4T1, it can modulate anti-tumor immunity by enhancing central memory T cell (Tcm) formation and reducing T cell exhaustion. Conclusion: These pre-clinical findings support the further investigation of incorporating DNMTi as a new immunotherapy modality for TNBC.