Supramolecular Modulation of Tumor Microenvironment through Pillar[5]arene-Based Host-Guest Recognition to Synergize Cancer Immunotherapy

Despite the tremendous breakthrough of immunotherapy,the low responserate and resistance of immune checkpoint inhibitors (ICIs) towardsolid tumors occur frequently. A highly hypoxic tumor microenvironment(TME) provides tumor cells with high concentrations of HIF-1 & alpha;and polyamines to evade immune cell destruction. Reprogramming ofan immunogenic TME has exhibited a brilliant future to boost immunotherapeuticperformances. Herein, a supramolecular nanomedicine (TAPP) is developed on the basis of host-guest molecular recognitionand metal coordination, showing the capability to remodel the immunosuppressiveTME. Tamoxifen (Tmx) and Fe3+ are encapsulatedinto TAPP to achieve the combination of chemotherapyand chemodynamic therapy (CDT). Tmx directly downregulatesHIF-1 & alpha;, and a pillar[5]arene-based macrocyclic host successfullyeliminates polyamines in tumors. Enhanced immunogenic cell death isachieved by Tmx and Fe3+, and the therapeuticefficacy is further synergized by immune checkpoint blockade (ICB)therapy. This supramolecular reprogramming modality encourages cytotoxicT lymphocyte infiltration, achieving pre-eminent immune response andlong-term tumor suppression.