Reverse Lipid Droplet Function for Hepatocellular Carcinoma Immunotherapy

Abstract Lipid droplet (LD)‐mediated organelle interactions promote tumor progression and immune evasion in tumors, but directly targeting LD remains challenging. Here, we developed a strategy to reverse LD function for hepatocellular carcinoma (HCC) immunotherapy. We first established a positive correlation between LD‐related proteins and poor prognosis in HCC patients. We then engineered F127‐modified, linoleic acid (LA)‐capped copper MOF nanoparticles (LCMF NPs). These NPs are recognized by CD36 and internalized into LDs. Whereafter, copper ions catalyze surface LA into radicals via Fenton reaction, triggering a polyunsaturated fatty acid peroxidation cascade. This chemical reaction reverses the protective effect of LDs on organelles into an oxidative damage effect. Mechanistically, this process induces significant DNA damage, upregulating key immunogenic cell death markers HMGB1 and calreticulin. In vivo, reversing LD function reshapes the immunosuppressive tumor microenvironment and inhibits growth of both primary and distant tumors. Overall, this LD functional reversal strategy establishes LD‐organelle networks as viable immunotherapy targets and offers a promising approach for treating metastatic tumors via organelle‐level metabolic disruption.