A major challenge in the use of chemotherapy and immunotherapy is hypoxia-induced progression of tumor cells. We aim to curb hypoxia using metal-based O2-producing nanomedicine. The key focus is therapeutic targeting of hypoxia-inducible factor 1α (HIF-1α), a major reactive oxygen species (ROS)-activated player that drives hypoxia-dependent tumor progression. Inhibition of tumor growth by blocking both HIF-1α and immune checkpoint molecules via ROS removal is a promising new strategy to avoid ROS-induced hypoxia signaling and boost antitumor immunity. Here, we investigated the synergistic effect of ultra-small platinum nanoparticles (Pt-nano) with dual functions of enzyme-mimicking catalysis and corrosion susceptibility to block hypoxia signaling of tumors. Ultra-small Pt-nano with highly corrosive susceptibility can efficiently catalyze ROS scavenging and promote oxygen accumulation for hypoxia reversal, leading to reduced HIF-1α expression. The unique corrosion susceptibility allows ultra-small Pt-nano to effectively exert platinum cytotoxicity, induce reversal of hypoxia-mediated immune suppression by promoting cytotoxic T-cell infiltration of tumors, and reduce the levels of tumoral immune checkpoint molecules and immunosuppressive cytokines. In combination with immune checkpoint blockade using monoclonal antibodies, nanoparticle-enabled enzyme-mimicking is a promising strategy for the enhancement of chemoimmunotherapeutic efficacy through the reversal of tumor hypoxia.
Keywords: HIF-1α; catalysis; chemoimmunotherapy; corrosion; tumor hypoxia; ultra-small Pt-nano.