COVER STORY: IRG1 is predominantly expressed in myeloid cells, particularly activated macrophages, where it encodes aconitate decarboxylase responsible for biosynthesis of the immunomodulatory metabolite Itaconate (ITA). Recent genetic and preclinical studies demonstrate that genetic ablation of Irg1 potentiates antitumor immunity and synergizes with immune checkpoint blockade. Despite its therapeutic potential, pharmacological strategies targeting IRG1 remain very limited. In this study, we employed a clinically approved LNP-siRNA therapy for selective IRG1 depletion in tumor-associated macrophages (TAMs). In both immunocompetent mice and human immune system (HIS) mice, LNP-siIRG1 enhances antitumor immunity partially by increasing the infiltration of cytotoxicity CD8+ T cells, without triggering systemic inflammation or off-target toxicity. Our findings validate LNP-siRNA targeting IRG1 as a safe and therapeutically viable approach for cancer therapy.
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