S100A8/A9 perturbation in bone marrow blunts antitumor immunity by promoting protumorigenic myelopoiesis in mouse models

作者：Wen Luo, Xingxing Su, Qiao Zhang, Zhongyu Wang, Jin Zheng, Yanan Li, Yang Fei, Dong Zeng, Xianghua Zeng, Guitong Lv, Mengyi Li, Jiani Huang, Haoran Zha, Ji Liu, Zhong Luo, Haixia Long, Bo Zhu · 发表于：Science Translational Medicine · 年份：2025 · DOI：10.1126/scitranslmed.adr3963 · 被引用次数：7 · 研究领域：S100 Proteins and Annexins、Immune Response and Inflammation、Immune cells in cancer

S100A8/A9 plays a critical role in the formation of an immunosuppressive tumor microenvironment. Therefore, it is important to identify inhibitors targeting S100A8/A9 to enhance antitumor immunity. However, systemic targeting of S100A8/A9 in clinical trials has shown minimal effects. Understanding the reasons underlying this underperformance is important for developing drugs targeting S100A8/A9 that could effectively reverse the immunosuppressive tumor microenvironment. In this study, using hematopoietic system-specific conditional knockout mice in heterotopic models of lung and colon cancer and systemic pharmacological interference, we demonstrated that S100A8/A9 perturbation in the hematopoietic system accelerates tumor progression by attenuating T cell-mediated antitumor immunity. Mechanistically, S100A8/A9 perturbation triggered myeloid-biased differentiation in the bone marrow by promoting the production of abnormal granulocyte-monocyte progenitors. The local release of S100A8/A9 inhibitors using a tumor-targeted drug delivery system exhibited antitumor potential by avoiding myelopoiesis-promoting effects. These findings reveal a mechanism underlying the limited efficacy of systemic S100A8/A9 inhibition and propose a targeted strategy to enhance antitumor effects.