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

Background/Objectives: Cyclophosphamide (CTX) treatment in vivo kills proliferating tumor cells by DNA crosslinking; however, the 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. Methods: A metastasized EO771 breast cancer model with chromosomal instability and bone marrow (BM) chimera approach were used in this study. Results: 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 BM-derived cells. Furthermore, the STING of type 1 conventional dendritic cells (cDC1s) and LysM+ cells and the IFN-I response of non-cDC1 myeloid cells are essential for CTX efficacy. We also found that the 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. Conclusions: Our study demonstrates 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 the chronic activation of intrinsic cGAS–STING caused by chromosomal instability.