cGAS and STING in Host Myeloid Cells Are Essential to Effective Cyclophosphamide Treatment of Advanced Breast Cancer

Cyclophosphamide (CTX) treatment in vivo kills proliferating tumor cells by DNA crosslinking, however, suppression of tumor growth by CTX in several murine models requires CD8+ T cells. Given that CTX induces DNA damage and type I interferon (IFN-I), we investigated the role of host cGAS and STING in the anti-tumor effect of CTX in vivo. Using a metastasized EO771 breast cancer model with chromosomal instability, we found that CTX therapy induces long-term survival of the mice with this outcome being dependent on CD8+ T cells and cGAS/STING of bone marrow (BM)-derived cells. Furthermore, STING of type 1 conventional dendritic cells (cDC1s) and LysM+ cells, and IFN-I response of non-cDC1 myeloid cells are essential for CTX efficacy. We also found that cGAS and STING of BM-derived cells positively modulate intratumoral exhausted and stem-cell-like CD8+ T cell populations under CTX treatment with the latter only being affected by cGAS. Our study elucidates that the CD8+-T-cell-dependent anti-tumor mechanisms of CTX critically involve the cGAS-STING-IFN-I axis, IFN-I response, and STING-independent cGAS function in host myeloid cells. These findings suggest the deployment of CTX in treating advanced solid tumor to bypass the often failed IFN-I production by tumor cells due to coping with chronic activation of intrinsic cGAS-STING caused by chromosomal instability.