Fig. 3

PI3K-AKT-mTOR inhibitors and CDK4/6 inhibitors orchestrate multiple effects on immune cells in the tumor immune microenvironment. The blue frame represents the antitumor immunity induced by PI3K-AKT-mTOR inhibitors. p110α and mTOR inhibitors decrease the number of MDSCs in tumors. The immunosuppressive function of MDSCs can be limited by p110δ and AKT inhibitors. p110δ inhibitors and long-term inhibition of mTOR also weaken Treg function. Moreover, p110γ and mTOR inhibitors promote the conversion of macrophages and mononuclear cells towards M1 phenotype. The function of CD8+ T cells is also enhanced by p110α, p110γ and p110δ inhibitors. p110α inhibitors suppress CD4+ T cells polarization towards Tregs, while pan-PI3K and AKT inhibitors are capable of selectively suppressing Treg proliferation. Additionally, pan-PI3K and p110γ inhibitors promote the tumor infiltration of T cells and B cells. Increased NK infiltration in tumors is also elicited by pan-PI3K inhibitors. Moreover, the function of DCs treated with mTOR inhibitors is significantly improved. The inhibition of PI3K-AKT-mTOR pathway also suppresses PD-L1 expression in BC cells, undermining PD-L1- mediated immunoresistance. The pink frame represents the protumor immunity induced by PI3K-AKT-mTOR inhibitors. pan-PI3K, p110β and mTOR inhibitors damage host defense mediated by macrophages, and p110β inhibition suppresses the cytotoxic function of neutrophils. p110δ inactivation shows an adverse effect on T cells and B cells. mTOR inhibitors can also suppress the effector function of T cells and NK cells, as well as promote Treg polarization. CDK4/6 inhibitors mainly induce antitumor immunity by improving the immunogenicity of BC cells and the antigen-presenting ability of DCs and macrophages. The CD8+/Treg ratio is also increased within tumors after CDK4/6 inhibitor treatment. The elevated level of PD-L1 in BC cells and immune cells mediated by CDK4/6 inhibitors supports the combined usage of CDK4/6 inhibitors with immune checkpoint inhibitor