KEY POINTS
- This translational study analyzed tumors from 72 patients with locally advanced, unresectable hepatocellular carcinoma receiving liver SBRT (45–60 Gy at 5–10 Gy per fraction), an immune checkpoint inhibitor, and bevacizumab.
- Microplastics were detected in 52 of 72 tumors (72%), including polyvinyl chloride in 37, polystyrene in 26, and polyethylene in 14. Only polyvinyl chloride was associated with poorer treatment response and progression-free survival, with a stronger association at higher intratumoral concentrations.
- In two orthotopic mouse models treated with 18 Gy in 3 fractions, polyvinyl chloride reduced radiotherapy efficacy without increasing tumor-cell proliferation or intrinsic radiosensitivity. The effect disappeared in immunodeficient mice and after CD8⁺ T-cell depletion.
- Mechanistically, irradiation increased H3K18 histone lactylation, HMGCR transcription, and cholesterol production, supporting stem-like precursor-exhausted CD8⁺ T cells. Polyvinyl chloride bound cholesterol and suppressed this radiotherapy-induced immune response.
- A high-cholesterol diet restored CD8⁺ T-cell stemness and radiotherapy response in polyvinyl chloride-exposed mice. Among 37 patients with polyvinyl chloride-positive tumors, higher pretreatment cholesterol was also associated with better outcomes, but this analysis was small and exploratory.
CLINICAL TAKEAWAY
The study identifies intratumoral polyvinyl chloride as a possible environmental modifier of radiotherapy response through altered cholesterol distribution and CD8⁺ T-cell differentiation. The mechanism is compelling but not clinically validated: the patient cohort was small, predominantly East Asian and hepatitis B-related, and all patients received combined systemic therapy. These findings do not justify cholesterol supplementation or changes in lipid management.