<p>Low immunogenicity remains a critical barrier to effective immunotherapy for hepatocellular carcinoma (HCC). Activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a promising strategy for HCC treatment; however, achieving specific activation of this pathway remains a major challenge. Herein, we report a novel biomimetic nanoplatform (PZ@M-T) that triggers ferroptosis to specifically activate the cGAS-STING pathway. This study utilized a hollow ZIF-8 metal-organic framework (MOF) coated with mesenchymal stem cell membrane (MSCm) as a biomimetic carrier of polyphyllin II (PPⅡ) functionalized with triphenylphosphine (TPP) via copper-free click chemistry for mitochondrial targeting. Acid-responsive PPⅡ release in the tumor microenvironment (TME) induced robust ferroptosis in HCC cells, eliciting mitochondrial stress to cause endogenous mitochondrial DNA (mtDNA) release, which specifically initiated the cGAS-STING pathway with the cooperation of Zn²⁺. This activation drove dendritic cell (DC) maturation, repolarized tumor-associated macrophages (TAMs) from the M2 to M1 phenotype, enhanced cytotoxic T cell infiltration, and suppressed regulatory T cells (Tregs), thereby collectively driving a robust anti-tumor immune response that significantly inhibited HCC progression. This innovative nanotherapeutic platform provides new promising strategy for tumor immunotherapy via specific activation of the cGAS-STING pathway and offers new insights into advanced chemo-immunotherapeutic approaches.</p> Graphical Abstract <p></p>