Targeting lipoprotein lipase-positive macrophage-driven GDF-15 expression alleviates cancer Cachexia in obese head...

Head and neck squamous cell carcinoma (HNSCC) is often associated with dysphagia and malnutrition, predisposing patients to cancer cachexia, which adversely affects postoperative prognosis and survival. Obese patients may exhibit underlying muscle wasting, a condition related to sarcopenic obesity, even when early body-weight loss is not prominent. Here, we identified a lipoprotein lipase-positive (LPL-positive) macrophage population in HNSCC that increased during tumor progression and was enriched in tumors from overweight/obese patients and high-fat diet-fed tumor-bearing mice. A high LPL-positive macrophage signature score based on TCGA-HNSC bulk transcriptomic and clinical follow-up data was associated with worse overall survival. LPL-positive macrophage-associated lipid metabolic changes were accompanied by increased growth differentiation factor 15 (GDF-15) secretion. Conditioned medium from LPL-overexpressing RAW264.7 macrophages and recombinant GDF-15 induced myotube atrophy and ferroptosis-related lipid peroxidation, whereas liproxstatin-1 or ferrostatin-1 partially reversed these effects. Systemic pharmacological lipase/LPL inhibition with Poloxamer 407 (P-407) or orlistat reduced LPL enzymatic activity, although these treatments also affected systemic lipid metabolism. Invalidation of LPL by siRNA in RAW264.7 cells further showed reduced GDF-15 secretion and attenuated conditioned-medium-induced myotube atrophy. These findings suggest that macrophage-associated LPL activity and GDF-15 contribute to muscle wasting in obese HNSCC and highlight a potential metabolic-immunologic axis involved in cancer cachexia. Using animal models, we further showed that systemic pharmacological lipase/LPL inhibition with P-407, particularly when combined with anti-PD-1 therapy, attenuated muscle wasting and improved the tumor immune microenvironment.