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.
背景/目的：环磷酰胺（CTX）在体内通过DNA交联作用杀伤增殖的肿瘤细胞；然而，CTX在多种小鼠模型中抑制肿瘤生长的作用依赖于CD8⁺ T细胞。鉴于CTX可诱导DNA损伤和I型干扰素（IFN-I）产生，本研究探讨了宿主cGAS和STING在CTX体内抗肿瘤效应中的作用。方法：本研究采用具有染色体不稳定性的转移性EO771乳腺癌模型及骨髓嵌合体技术。结果：我们发现CTX治疗可诱导小鼠长期存活，该效应依赖于CD8⁺ T细胞及骨髓来源细胞的cGAS/STING通路。此外，1型经典树突状细胞（cDC1）和LysM⁺细胞的STING，以及非cDC1髓系细胞的IFN-I应答对CTX疗效至关重要。我们还发现，在CTX治疗下，骨髓来源细胞的cGAS和STING正向调控肿瘤内耗竭性及干细胞样CD8⁺ T细胞亚群，其中后者仅受cGAS影响。结论：本研究证实CTX依赖CD8⁺ T细胞的抗肿瘤机制关键涉及宿主髓系细胞中的cGAS–STING–IFN-I轴、IFN-I应答以及不依赖STING的cGAS功能。这些发现提示，在治疗晚期实体瘤时应用CTX，可规避因染色体不稳定性导致肿瘤细胞内源性cGAS–STING持续激活而常出现的IFN-I生成障碍。
肿瘤(癌症)患者之家