Bio-orthogonal truncated NKG2D ligand-based nano-igniter unleashes a self-sustaining antitumor immune circuit via NK cell activation.

Despite the crucial role of natural killer (NK) cells in initiating antitumor immune circuits, their efficacy is limited by tumor immune evasion mechanisms, including low surface density or proteolytic shedding of activating ligands and immunosuppression. Here, we constructed a bioorthogonal truncated NKG2D (natural killer group 2, member D) ligand-based nano-igniter (ZIL15-D-trMULT1) to synchronously enhance NK cell recognition and function, thereby igniting antitumor immune circuits. This system incorporates a truncated NKG2D ligand (trMULT1) lacking the cleavable α3 domain while retaining the NKG2D-binding α1/α2 domains, conjugated to dibenzocyclooctyne (DBCO) for bioorthogonal tagging of azide-modified tumor cells. Concurrently, interleukin-15 (IL-15) was encapsulated within zeolitic imidazolate frameworks (ZIF-8) for responsive release, sustaining NK cell function and upregulating NKG2D receptor expression. This synergistic design created a positive feedback loop for NK cell recognition and activation. Consequently, this strategy suppressed multiple tumor types and improved the immune microenvironment. Mechanistically, both innate and adaptive immunity were mobilized by orchestrating crosstalk between dendritic cells and T cells, facilitated by NK cell-derived chemokine secretion. In combination with anti-PD-1 antibody, ZIL15-D-trMULT1 induced durable immune memory, restraining distal tumor growth and lung metastasis. Our work unveils a self- sustaining immune circuit triggered by NK cells through upregulating the un-cleavable NKG2D ligand density, providing a robust strategy against solid tumors.