Polyvinyl Chloride Promotes Radioresistance in Hepatocellular Carcinoma by Inhibiting Radiotherapy-Induced CD8⁺ T Cell Differentiation

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 altered cholesterol localization and affected CD8⁺ T cell differentiation, which maintained a ‘cold’ tumor immune microenvironment (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.