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.