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Polyvinyl Chloride Promotes Radioresistance in Hepatocellular Carcinoma by Inhibiting Radiotherapy-Induced CD8⁺ T Cell Differentiation
Summary
Researchers found that PVC microplastics, detected in 72% of 72 hepatocellular carcinoma tumor samples, promoted resistance to radiotherapy by inhibiting CD8+ T cell differentiation, with mechanistic analysis revealing that radiotherapy-enhanced histone lactylation upregulated HMG-CoA reductase in cancer cells to facilitate cholesterol accumulation and impair immune-mediated tumor killing.
Abstract Radiotherapy (RT) has emerged as one of the primary treatment modalities for intermediate and advanced hepatocellular carcinoma (HCC). However, RT resistance remains widespread. Microplastics (MPs) have been detected in various tumors and may disrupt immune responses. However, evidence regarding the role of MPs in RT is scarce. Several MPs were identified in 72% (52/72) of HCC samples, among which polyvinyl chloride (PVC) impaired RT efficacy. Mechanistically, RT enhanced histone lactylation, which promoted the transcription of HMG-CoA reductase in HCC cells, thereby facilitating cholesterol synthesis and reinforcing CD8+ T cell stemness. PVC was altered cholesterol localization and disturbed CD8⁺ T cell differentiation, which maintained a ‘cold’ TIME. A high-cholesterol diet restored CD8+ T-cell stemness and improved the therapeutic response to RT in PVC-infiltrated HCC. We demonstrated that PVC could promote RT resistance. Targeting cholesterol metabolism may represent a potential combinatorial strategy to enhance the efficacy of RT in PVC-infiltrated HCC.