An Activated Gasdermin Mimicking Polymer for Antitumor Immunity.

Abstract

Synthetic polymers with protein-like functions have the potential to revolutionize the way of modulating physiological processes. Pyroptosis, a form of gasdermin-driven programmed necrosis, is widely viewed as a promising strategy to ignite antitumor immunity. Yet, the intrinsic silence or absence of gasdermins (GSDMs) in tumor cells and the complex intracellular activation process limit its wider applications. Inspired by the pore-forming mechanism of activated N-terminal gasdermins (N-GSDMs), we here develop a synthetic zinc coordination polymer, DPDPA-Zn, that functions similarly to N-GSDMs. DPDPA-Zn can selectively adhere to anionic phospholipid-containing liposomes and form oligomeric structures on their surfaces. This oligomerization incites membrane curvature and effectively perforates the acidic phospholipid-containing liposomes. Once internalized by mammalian cells, DPDPA-Zn functions like N-GSDMs by acting as an executor of pyroptosis, effectively inducing cell death through an N-GSDM-independent pyroptosis. Local treatment with DPDPA-Zn significantly reduces tumor burden in mice challenged with breast, colorectal, and melanoma cancers. Moreover, DPDPA-Zn-induced pyroptosis leads to the release of cytosolic inflammatory cytokines and tumor antigens, effectively activating robust systemic antitumor immunity and protecting mice against subsequent tumor rechallenges. Collectively. This N-GSDM-mimicking polymer possesses enormous potential for addressing the lack of GSDMs in cancer cells and activating a robust <i>in situ</i> vaccine effect.