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.