Hypoxia‐Responsive Nanoscale Coordination Polymer Enhances the Crosstalk Between Ferroptosis and Immunotherapy

Abstract

The immunosuppressive tumor microenvironment (TME) severely limits the clinical applications of cancer immunotherapy. Herein, a hypoxia‐responsive delivery system is constructed simply by coordinating ferric (Fe3+) with mitoxantrone (MTO), sulfasalazine (SAS), and hypoxia‐sensitive dopamine derivative of polyethylene glycol (PEG) using “one‐pot” reaction for the “closed‐loop” synergistic enhancement of ferroptosis and immunotherapy. Hypoxia‐sensitive PEG ensures the integrity of delivery system in circulation to prevent the premature leakage of drugs, and the detachment of PEG in the interior hypoxic TME can facilitate the deep penetration and the subsequent tumor uptake. The released iron and MTO induce the generation of reactive oxygen species (ROS), while SAS inhibits the elimination of lipid peroxides by inhibiting SLC7A11 subunit of glutamate‐cystine antiporter, which synergistically induces immunogenic ferroptosis to promote dendritic cells maturation and T cells activation. The activated CD8+ T cells then release interferon γ (IFN‐γ) and in turn enhance ferroptosis by downregulating the expression of SLC7A11. As a result, the “closed‐loop” synergistic enhancement between ferroptosis and immunotherapy significantly prevents tumor growth and prolonged survival time of tumor‐bearing mice with no obvious systemic toxicity. The excellent therapeutic effect together with the scalable synthesis and controllable quality will promise its translation to clinic as a novel immunotherapy.

Stimuli-Responsive Polymeric Nanomedicine for Enhanced Cancer Immunotherapy

“…Cai et al synthesized self-assembled nanoparticles based on azobenzene-conjugated dopamine (Figure 8). 132 They encapsulated mitoxantrone (MTO) and sulfasalazine (SAS) within these nanoparticles (PAD@MS) to induce ferroptosis. Under hypoxia-mimicking conditions, using 10 mM sodium dithionite as an oxygen scavenger, the release of MTO and SAS was significant, with a substantial amount being released until 6 h. In contrast, under normal conditions, 40% of MTO and SAS were released until 24 h, suggesting that hypoxic mimicking conditions facilitate a faster and more extensive release of the drugs from the nanoparticles.…”

“…(h) Survival analysis of mice following indicated treatments. Reproduced with permission from ref . Copyright 2023 Wiley.…”

Nanoparticles Synergize Ferroptosis and Cuproptosis to Potentiate Cancer Immunotherapy

“…As a new class of hybrid core-shell nanoparticles, nanoscale coordination polymers (NCPs) can incorporate hydrophilic molecules in the core and hydrophobic molecules on the shell to significantly improve their blood circulation and tumor accumulation, providing a versatile platform for delivering synergistic combination treatments. [28][29][30][31] Since nanoparticle-mediated cuproptosis was recently shown to up-regulate programmed death-ligand 1 (PD-L1) expression of cancer cells and reprogram the immunosuppressive tumor microenvironment (TME) [32][33][34] and cuproptosis can be enhanced by ferroptosis inducers, [35] we anticipate that NCP-mediated ferroptosis and cuproptosis will synergize with immune checkpoint blockade (ICB) to elicit potent antitumor immunity.…”