LIPA-driven reprogramming of tumor-associated macrophages shapes an immunosuppressive microenvironment in...

Osteosarcoma is a highly aggressive malignant tumor with limited treatment options, and the role of triglyceride metabolism in tumor progression remains poorly understood. Mice fed a high-fat diet exhibited accelerated tumor growth and increased lung metastasis. A risk score model based on triglyceride metabolism-related genes demonstrated strong predictive performance, with LIPA emerging as a critical gene. LIPA was identified as being negatively correlated with survival and was found to be an independent risk factor. High LIPA expression was associated with an immunosuppressive macrophage phenotype and altered immune infiltration in the tumor microenvironment. Single-cell sequencing revealed a distinct subset of macrophages characterized by LIPA expression, which was consistently validated in human, mouse, and patient-derived xenograft osteosarcoma samples. Functional studies demonstrated that LIPA⁺ macrophage promoted tumor progression and facilitated T cell suppression. Structure-based virtual screening and validation identified the FDA-approved drug Glecaprevir as a potential LIPA inhibitor.