Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer and new treatments are urgently needed for this disease. As single-agent therapies, CDK4/6 and PI3Kα inhibitors have shown little evidence of clinical activity in TNBC. Interestingly, we have shown that dual blockade of CDK4/6 and PI3Kα is synergistically effective against multiple TNBC models. Combined treatment was shown to significantly improve disease control in human xenograft models compared with either monotherapy. This combination treatment exerts TNBC disease control by significantly increasing apoptosis, cell cycle arrest and tumor immunogenicity as well as generating immunogenic cell death in human TNBC cell lines. Combined CDK4/6 and PI3Kα inhibition significantly increased tumor-infiltrating T cell activation and cytotoxicity and decreased frequency of immunosuppressive myeloid-derived suppressor cells in a syngeneic TNBC mouse model. Notably, combined CDK4/6 and PI3Kα inhibition, along with inhibition of immune checkpoints PD-1 and CTLA-4 induced complete and durable regressions (>1 year) of established TNBC tumors in vivo. Overall, our results illustrate convergent mechanisms of CDK4/6 and PI3Kα blockade on cell cycle progression, DNA damage response and immune-modulation and may provide a novel therapeutic approach for TNBC.