Manganese-Doped Nanoparticles with Hypoxia-Inducible Factor 2α Inhibitor That Elicit Innate Immune Responses against von Hippel–Lindau Protein-Deficient Tumors

The von Hippel–Lindau (VHL) tumor suppressor gene product, pVHL, is frequently deficient in a variety of human cancers. In addressing the treatment of pVHL-deficient tumors, hypoxia-inducible factor 2α (HIF-2α) has risen as a promising therapeutic target, culminating in the development of specific inhibitors like PT2385 and its analogues. Nonetheless, the absence of targeted delivery capabilities in these inhibitors heightens the risk of on-target toxicities. To mitigate these limitations, we have engineered a nanoparticle, termed PMMF (PT/MMSN@DSPE-PEG-FA), capable of delivering both a HIF-2α antagonist (PT2385) and manganese directly to tumor sites. PMMF has shown effective targeting of pVHL-deficient clear-cell renal cell carcinoma and melanoma, leading to significant therapeutic benefits and alleviating hypoxic and immunosuppressive traits of the tumor microenvironment. Functionally, PMMF boosts the cyclic GMP–AMP synthase–stimulator of interferon genes signaling pathway, which, in turn, stimulates a robust innate immune response. This response activates natural killer (NK) cells and CD8⁺ T lymphocytes while curbing the infiltration of regulatory T cells. Notably, the therapeutic efficacy of PMMF is markedly reduced when NK cells are blocked but not affected by neutrophil blockade, highlighting the critical role of NK cells in PMMF-induced antitumor immunity. Additionally, the safety profile of PMMF showed minimal systemic post-treatment cytotoxicity. In summary, our findings position PMMF as a promising platform for treating tumors with pVHL deficiency and underscore the therapeutic potential of metalloimmunotherapy.