Inorganic Nanomaterials can Promote or Inhibit Tumor Metastasis Depending on Tumor Microenvironment Composition

ABSTRACT The growing application of engineered nanomaterials (NMs) in cancer imaging and therapy highlights the need to better understand their effects on tumors and the tumor microenvironment (TME). Previous studies have reported conflicting findings, suggesting that NMs can either enhance or suppress tumor metastasis. In this study, we investigated the impact of gold (Au) and silica‐coated gold (Au Sil ) nanomaterials on metastatic progression in two triple‐negative breast cancer (TNBC) models. Despite having similar size and surface characteristics, the NMs produced distinct, tumor‐specific effects, resulting in either increased or decreased metastatic dissemination depending on the experimental context. Further analysis of the TME revealed several factors influencing these outcomes. Both Au and Au Sil NMs increased endothelial permeability, while Au NMs also stimulated cancer cells to produce anti‐angiogenic factors. In both cases, higher levels of hypoxic tumor‐associated macrophages were associated with reduced endothelial vessel maturity. Importantly, NM‐induced increases in metastasis could be mitigated through pharmacological vessel normalization or inhibition of hypoxia‐related signaling pathways. Overall, these findings demonstrate that Au and Au Sil nanomaterials exert context‐dependent effects on metastasis by modifying the TME, while also identifying strategies to improve their safe and effective use in cancer applications.