A metal-quercetin-histidine co-coordinated nanoparticle enhances cancer photothermal therapy via reshaping immunosuppressive tumor microenvironment

Photothermal therapy (PTT) relying on photothermal conversion agents (PCAs) to generate local hyperthermia and eliminate tumors is considered as a high-efficiency localized treatment method for cancer. However, PTT inadvertently exacerbates tumor immune evasion and recurrence, and leads to tumor metastasis through producing excessive free radicals and inflammatory responses at the tumor microenvironment (TME). Facing this challenge, here, we designed metal-quercetin-histidine co-coordinated nanoparticles (FQH NPs) as a multifunctional PCA with capacity of reversing immunosuppressive TME and activating the "cold" tumor to "hot". Through co-coordination guided band-ligand-to-metal charge transfer (LMCT), the self-assembled FQH NPs exhibit robust photothermal conversion capabilities, efficiently scavenge various ROS generated during PTT, and decrease excretion of pro-inflammatory factor interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Furthermore, FQH NPs remarkably decrease the expression of programmed death ligand 1 (PD-L1) on cancer cells, thereby increasing activation of T cells in tumors. Combining with the immunogenic cell death (ICD) effect during PTT, this immune-checkpoint inhibition effect conquers the "cold" orthotopic breast cancer, prevents liver/lung metastasis, and also inhibits the growth of distal tumors through immune memory effect. It offers perspectives and potential avenues for improving photothermal cancer therapy.