Polyvinyl chloride promotes radioresistance in hepatocellular carcinoma by inhibiting radiotherapy-induced CD8⁺ T cell differentiation.

Radiotherapy is standard-of-care treatment for intermediate and advanced hepatocellular carcinoma (HCC); however, resistance remains widespread. Microplastics are detectable in various tumors and may disrupt immune responses, but evidence regarding the role of microplastics in radiotherapy is scarce. Here we show that various types of microplastics are detectable in 52 of the 72 HCC samples we examine, but only polyvinyl chloride (PVC) impairs radiotherapy efficacy. Mechanistically, irradiation enhances histone lactylation, which promotes transcription of HMG-CoA reductase in HCC cells, thereby facilitating cholesterol synthesis and reinforcing CD8+ T cell stemness. PVC alters cholesterol localization and affects CD8⁺ T cell differentiation, which results in the maintenance of an immunologically cold tumor immune microenvironment. A high-cholesterol diet restores CD8+ T-cell stemness and improves therapeutic response to radiotherapy in PVC-infiltrated HCC. Targeting cholesterol metabolism may represent a potential combinatorial strategy to enhance the efficacy of radiotherapy in PVC-infiltrated HCC.