CD36‐Pocket Targeting Induces Metabolic Collapse and Disulfidoptosis for Sonodynamic Immunometabolic Therapy of Liver Cancer

ABSTRACT Obesity‐driven lipid accumulation in hepatocellular carcinoma (HCC) establishes a coupled metabolic‐immunosuppressive niche that fuels tumor progression and undermines anti‐tumor immunity. Through multiplexed immunofluorescence profiling of clinical HCC tissues stratified by visceral adiposity, we explicitly map this lipid‐immunosuppressive landscape and demonstrate that fatty acid translocase CD36 overexpression directly correlates with FoxP3 + Treg infiltration and CD8 + T cell exclusion, defining a clinically actionable immunometabolic vulnerability. To therapeutically exploit this vulnerability, we engineer an AI‐designed, structure‐guided CD36‐occluding nanoplatform (LAIBP) with intrinsic ultrasound‐responsive sonodynamic capability. Mechanistically, LAIBP selectively blockades CD36‐mediated exogenous lipid influx to impose metabolic vulnerability; subsequent ultrasound activation triggers a spatiotemporally controlled oxidative burst, driving disulfidoptosis‐like cell death through NADPH depletion, redox imbalance, and cytoskeletal collapse in the lipid‐replete tumor microenvironment. Transcriptomic analysis and protein‐level validation indicate coordinated metabolic, redox, and immune‐associated changes, with G protein‐coupled receptor (GPCR)‐associated phosphatidylinositol 3‐kinase (PI3K)/ serine/threonine‐protein kinase (Akt)/ Serine/threonine‐protein kinase mTOR signaling and the cystine/glutamate transporter (SLC7A11) ‐ phospholipid hydroperoxide glutathione peroxidase(GPX4) axis emerging as pathways associated with the observed metabolic‐redox response. In obesity‐associated implanted HCC mouse models, LAIBP combined with ultrasound irradiation suppresses tumor growth, reduces intratumoral lipid accumulation, and is associated with remodeling of the tumor immune microenvironment. Collectively, this work supports a clinically grounded rationale and a nanotherapeutic framework for further immunometabolic investigation in obesity‐associated HCC. Conclusion The LAIBP nanoplatform, via the integrated paradigm of “metabolic entry blockade + redox homeostasis disruption + exogenous trigger amplification”, induces metabolic collapse and disulfidoptosis‐like damage in HCC cells and is associated with remodeling of the antitumor immune microenvironment. This work supports a candidate sonodynamic, immunometabolism‐associated strategy for obesity‐associated HCC.