S100A8/A9 perturbation in bone marrow blunts antitumor immunity by promoting protumorigenic myelopoiesis in mouse models
Menée à l'aide de modèles murins de cancer du poumon ou de cancer du côlon, cette étude met en évidence un mécanisme par lequel l'inhibition systémique de l'expression des protéines S100A8/A9 de la moelle osseuse réduit l'immunité antitumorale en favorisant la myélopoïèse protumorigène et démontre que la délivrance ciblée de nanoparticules chargées en inhibiteurs de S100A8/A9 supprime la croissance tumorale
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. Systemic S100A8/A9 inhibition triggers immunosuppressive myeloid cell differentiation, whereas tumor-targeted delivery restores tumor control. The heterodimeric, calcium-binding proteins S100A8 and S100A9 are involved in forming an immunosuppressive tumor microenvironment, but targeting them with systemically acting inhibitors has not been effective in clinical trials. Using hematopoietic lineage-specific S100a8 knockout mice in models of lung and colon cancer, Luo et al. found that the loss of S100A8/A9 increased the production of immunosuppressive granulocyte-monocyte progenitors in bone marrow and increased tumor burden. The release of S100A8/A9 inhibitors using tumor-targeted local delivery of inhibitor-loaded nanoparticles enabled the inhibition of tumor growth while avoiding undesirable effects on myelopoiesis. These findings support the translational potential of increasing the efficacy of S100A8/A9 inhibition through the targeted delivery of S100A8/A9 inhibitors. —Amy E. Baek
Science Translational Medicine , article en libre accès, 2025