Two step promotion of a hot tumor immune environment by gold decorated iron oxide nanoflowers and light-triggered mild hyperthermia

Nanoparticle-mediated photothermal therapy (PTT) is an emerging modality to treat tumors with both spatial and temporal control provided by light activation. Gold decorated iron oxide nanoflowers (GIONF) are good candidates for PTT due to their biocompatibility, biodegradability and light-to-heat conversion. Profound changes in the tumor immune environment might be early induced by the gold and iron oxide metallic agents in addition to the photothermal effects. This study aims to elucidate the outcome of GIONF on their own, and of GIONF-induced mild hyperthermia in the tumor immune infiltrate in a murine model of triple negative breast cancer. First we explored the effects of 24 h GIONF exposure on bone-marrow derived macrophages (BMDM), revealing significant effects on the BMDM phenotype and secretion, 6 days post-incubation, with important downregulation of several cytokines and MHCII expression, predominantly towards a pro-inflammatory response. Intratumoral administration of GIONF promoted an increase in monocyte recruitment at day 1 post-administration, shifting towards a pro-inflammatory anti-tumor microenvironment with lower Treg population and a 4 fold lower CD4/CD8 ratio compared to the control at day 12. On top of the GIONF effects, mild hyperthermia (43 degrees C for 15 min), although it does not induce significant changes in tumor growth, resulted in an additional increase of CD8+ T lymphocytes and pro-inflammatory cytokines. The combination of a timely controlled immune response to GIONF and to mild hyperthermia could be used as a remotely triggered adjuvant treatment to immunotherapy approaches at the best favorable time-window.