Abstract
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.
Highlights
Tumor hypoxia can elicit dysfunction of the mitochondrial respiratory chain reaction, and this process results in the excess production of reactive oxygen species (ROS).[1]
After the preparation of the fresh caged Pt-nano (CPN) and double-caged Ptnano (DCPN), we purposely exposed the dry powder of CPN and DCPN under an oxygen atmosphere for several hours, which will increase the corrosion susceptibility of the ultra-small Pt-nano
The results suggest that the enzyme-mimicking catalysis of corrosion-activated platinum nanoparticles (Ptnano) will not exacerbate tumor progression via ROS induction during the hypoxia adaption of tumor cells, which might provide a beneficial effect for tumor treatment
Summary
Tumor hypoxia can elicit dysfunction of the mitochondrial respiratory chain reaction, and this process results in the excess production of reactive oxygen species (ROS).[1] Increased ROS levels can stabilize hypoxia-inducible factor 1α (HIF-1α) through the activation of a cellular energy sensor.[2] HIF-1α is a master regulator of cells and tissues in response to hypoxia and is a key player in tumor initiation and progression.[3] HIF-1α protein expression is regulated by O2-dependent post-translational modification, including hydroxylation and ubiquitination, leading to proteasomal degradation.[4] Promoter regulation of HIF-1α transcription is a crucial mechanism in controlling the HIF-1α expression in response to reduced O2 levels.[5] High levels of ROS can trigger multiple downstream signaling pathways of HIF-1α and eventually enhance tumor growth.[6] Tumor hypoxia may lead to other adverse events, including angiogenesis and abnormal glycolysis, which can enhance the complexity of the tumor microenvironment (TME) and result in hypoxia-induced drug resistance.[3,7−9]
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