Turning Fluvastatin into a supramolecular immuno-sensitizer towards augmented tumor immunotherapy

Although the clinical application of immune checkpoint blockers has been improving survival and living quality for patients with advanced malignant tumors, their anti-cancer action always suffered from the hypoxic tumor microenvironment (TME). To develop a tumor-targeting therapeutic for the redressment of the hypoxia with clinical translation potential, Fluvastatin, a FDA-approved inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, was used to suppress mitochondrial respiration through the synthesis inhibition of coenzyme Q. Towards tumor targeting, a de novo mild and efficient strategy was developed to construct a size-tunable nanostructure with spherical morphology through the supramolecular self-assembly between the partially reductive HSA and the hydrophobic Fluvastatin. As expected, this Albumin-bound Fluvastatin (AB-Flu) nanomedicine significantly enriched the drug concentration in tumor cells, and resurrected the action of Fluvastatin to redress the hypoxia of TME. As a result, AB-Flu normalized T-cell-relative immune microenvironment, thereby effectively sensitizing the potency of Anti-PD1 against colorectal cancer in the MC38 homograft mouse model and the humanized patient-derived xenograft (PDX) mouse model, while keeping a favorable profile of safety. Collectively, the supramolecular self-assembled strategy for the AB-Flu construction not only provided a new drug candidate for redressing the hypoxia in TME and augmenting tumor immunotherapy consequently, but also offered a promising tool to develop a new class of HSA-derived supramolecules for the site-specific precise therapy of multifarious tumors.