A Nanoplatform to Amplify Apoptosis-to-Pyroptosis Immunotherapy via Immunomodulation of Myeloid-Derived Suppressor Cells

Abstract

Pyroptosis is a programmed cell death to enhance immunogenicity of tumor cells, but pyroptosis-based immunotherapy is limited due to the immune escape involving myeloid-derived suppressor cells (MDSCs). Therefore, designing a nanoplatform to not only trigger apoptosis-pyroptosis transformation but also combat the MDSC-based immune escape is of great significance. As a proof-of-concept study, here, we designed a metal organic framework (MOF)-based nanoplatform to tailor the pyroptosis immunotherapy through disrupting the MDSC-mediated immunosuppression. By pH-responsive zeolitic imidazolate framework-8 (ZIF-8) modified with hyaluronic acid (HA), the chemotherapeutic drug mitoxantrone (MIT) and DNA demethylating agent hydralazine (HYD) were successfully co-encapsulated into ZIF-8 for achieving (M+H)@ZIF/HA nanoparticles. This nanoplatform demonstrated a powerful apoptosis-to-pyroptosis transformation with a potent disruption of MDSC-mediated T cell paralysis via reducing immunosuppressive methylglyoxal by HYD. Overall, our two-pronged nanoplatform (M+H)@ZIF/HA can switch the cold tumor into an arsenal of antigens that stimulate robust immunological responses, while suppressing immune escape, collectively triggering vigorous cytotoxic T cell responses with remarkable tumor elimination and building a long-term immune memory response against metastasis.

Nanomaterials: small particles show huge possibilities for cancer immunotherapy

“…However, this mediated tumor immunotherapy is limited by myeloid-derived suppressor cells (MDSCs). Based on this study, Luan et al [ 238 ] proposed a nanoparticle that could disrupt MDSC immunosuppression and induce cellular pyroptosis with high efficiency. Zn 2+ -based pH-responsive ZIF-8 (zeolite imidazolium framework-8) was used as a carrier for the nanomaterials, and (M + H)@ZIF was obtained by loading the drug MIT (mitoxantrone) and the DNA demethylating agent HYD (Hydralazine) (Fig.…”

Nanoscale Zeolitic Imidazolate Framework (ZIF)–8 in Cancer Theranostics: Current Challenges and Prospects

“…HYD upregulated Gasdermin E, while MIT induced caspase–3 activation, causing cell death. In addition, HYD inhibited methylglyoxal, a metabolic marker of myeloid–derived suppressor cells, which were involved in immune paralysis of CD8+ T cells [ 105 ]. By co–loading HYD and MIT on ZIF–8 nanoparticles, immune escape was suppressed and antitumor immune effects were enhanced ( Figure 6 B).…”

“…Copyright 2020 Elsevier Ltd. ( B ) ZIF–8 nanoplatforms for immunotherapy/chemotherapy. Reprinted with permission from Ref [ 105 ]. Copyright 2021 American Chemical Society.…”

Evoking pyroptosis with nanomaterials for cancer immunotherapy: Current boom and novel outlook

“…Recent studies have improved our understanding of the mechanisms of pyroptosis to a considerable extent, with studies being increasingly devoted to transforming immunologically silent apoptosis [102] into immunoinflammatory pyroptosis so as to transform the "cold" TME into a "hot" TME, particularly in combination with immunotherapy, which has promising applications in tumor treatment [59]. To achieve this, Zhou et al [103] constructed a pH-responsive nanoreactor (mitoxantrone (MIT) + hydrazine (HYD)/hyaluronic acid (HA) + zeolitic imidazolate framework-8 (ZIF-8)), composed of a pH-responsive ZIF-8 decorated with HA, which prolongs the circulation time of the nanoreactor, in addition to carrying both the chemotherapeutic drug MIT and the DNA demethylating agent HYD. When the nanoreactor was disassembled, HYD upregulated the expression of GSDME through epigenetic alterations, whereas MIT triggered tumor cell pyroptosis by mediating the activation of caspase-3.…”