Akt inhibition enhances the antitumor efficacy of immune checkpoint blockades and radiotherapy in a syngeneic breast cancer model

Immune checkpoint blockades (ICBs) have limited efficacy against immunologically cold breast cancers. Although radiotherapy (RT) can potentiate antitumor immunity, many patients fail to benefit, partly due to activation of immunosuppressive cells. Given the ability of PI3K inhibition to regulate immunosuppressive repertoires, we hypothesized that inhibition of Akt, a key effector of PI3K, could enhance the efficacy of RT and ICBs. In this study, we investigated antitumor effects and immune cell phenotypes in 4T1 syngeneic triple-negative breast cancer (TNBC) models treated with RT, ICBs, and an Akt inhibitor. RT + αPD-L1 + Akt inhibitor most reduced tumor size and lung metastases. The Akt inhibitor increased the M1/M2 macrophage ratio and the proportion of CD86⁺ dendritic cells (DCs). Interestingly, RT + αPD-L1 increased M2 macrophages, while adding the Akt inhibitor partially restored M1/M2 balance. When combined with RT + αPD-L1/αCTLA-4, Akt inhibition further elevated the M1/M2 ratio and CD86⁺ DC frequency and reduced monocytic myeloid-derived suppressor cells (M-MDSCs). These findings suggest that addition of an Akt inhibitor to RT and ICBs leads to a less immunosuppressive tumor microenvironment by modulating myeloid cells. Taken together, Akt inhibition could be a viable strategy to overcome therapeutic resistance of ICBs and RT in breast cancer.