A lymph node-targeted nanoplatform reprograms metabolic and immune microenvironments via dual ACSL3/4 inhibition in...

Lymph node metastasis in hepatocellular carcinoma depends heavily on lipid metabolic reprogramming, wherein the acyl-CoA synthetase long-chain family members ACSL3 and ACSL4 act as central survival hubs. However, single-target interventions often fail to curb metastasis due to the inherent metabolic plasticity and flexibility of tumors. Here, through retrospective clinical cohort analyses, we discovered that ACSL3 and ACSL4 are markedly co-upregulated in metastatic lymph nodes, driving malignant progression and poor prognosis. Driven by this finding, we engineered a lymph node-targeted nanoplatform (siACSL3/4@Gal-LNP) for the dual-gene inhibition, aiming to modulate lipid metabolism and validate its feasibility as a therapeutic target. Utilizing this platform, we elucidated an integrated metabolic axis comprising the ACSL3-mediated "metabolic shield" for ferroptosis resistance and the ACSL4-driven "metastatic spear" for enhanced invasion. Notably, we found that single-target inhibition of ACSL4 triggers a compensatory upregulation of ACSL3, which decreases the ferroptosis sensitivity of tumor cells. Leveraging this dual-inhibition capability, the siACSL3/4@Gal-LNP nanoplatform effectively overcomes adaptive escape, directly inducing a profound lipid collapse. This intervention reshapes membrane biophysics to suppress invasion and triggers ferroptosis. Concurrently, it depletes Tregs and downregulates PD-L1, effectively reprogramming the immunosuppressive microenvironment toward an immune-active state. Furthermore, we verified that siACSL3/4@Gal-LNP could greatly sensitize metastatic tumors to low-dose radiotherapy by blocking metabolic escape pathways, and markedly overcome tumor cell resistance to ferroptosis. Therefore, this "dismantling shield and breaking spear" strategy effectively disrupts the lipid metabolic plasticity and remodels the immune microenvironment, providing a highly potent and effective therapeutic strategy for lymph node metastatic tumors.