<p>Lung cancer remains a leading cause of cancer-related mortality worldwide, with bone metastasis presenting a significant challenge due to its association with severe skeletal complications and therapy resistance. This study investigates the role of bone marrow adipocytes (BMAs) in modulating fatty acid metabolism within the bone metastatic niche of lung cancer. Utilizing single-cell sequencing and in vitro co-culture models, we identified critical interactions between BMAs and metastatic lung cancer cells that enhance fatty acid metabolism, promoting tumor survival and drug resistance. To target this metabolic axis, we screened a library of fatty acid synthesis inhibitors, and developed a nanoparticle system encapsulating kaempferol, and cisplatin, surface-modified with poly-aspartic acid for efficient bone targeting. The nanoparticles release their therapeutic payload in the acidic tumor microenvironment, disrupting fatty acid metabolism and overcoming chemoresistance. Our findings highlight the metabolic reprogramming driven by BMAs in bone metastasis and propose a novel therapeutic strategy to improve outcomes for patients with metastatic lung cancer.</p>