Remodeling the tumor microenvironment by vascular normalization and GSH-depletion for augmenting tumor immunotherapy

Remodeling tumor microenvironment (TME) is a very promising and effective strategy to enhance the effects of chemotherapy, photodynamic therapy, and immunotherapy. Normalization of tumor vasculature as well as depletion of glutathione (GSH) can improve the TME. Here, we developed a novel therapeutic nanoparticle functional enzyme ultra QDAU5 nanoparticles (FEUQ Nps) based on a fluorescence-on and releasable strategy by combining a vascular normalization inducer, a GSH depleting agent, and an activated fluorophore. In which the cleavage of disulfide bonds releases active molecules that induce vascular normalization and improve the hypoxic microenvironment. In addition, it may deplete GSH in cancer cells, thus inducing the production of reactive oxygen species (ROS) and lipid peroxide (LPO) and promoting iron toxicity. It may also lead to endoplasmic stress and release of calmodulin, which activates the immune system. Meanwhile, quenched fluorophores are turned on in the presence of galactosidase (GLU) for tumor-specific labeling. In summary, we developed novel therapeutic agent nanoparticles with the function of vascular normalization inducers to achieve specific labeling of hepatocellular carcinoma while exerting efficient antitumor effects in vivo.