2. Academic Validation
  3. Serum starvation-induced cholesterol reduction increases melanoma cell susceptibility to cytotoxic T lymphocyte killing

Serum starvation-induced cholesterol reduction increases melanoma cell susceptibility to cytotoxic T lymphocyte killing

  • Sci Rep. 2025 May 26;15(1):18364. doi: 10.1038/s41598-025-00586-2.
Miaomiao Hou 1 2,  Longtao Ji 3,  Dimin Li 1 2,  Qian Xiao 3,  Xiao Hu 4 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
  • 2 Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China.
  • 3 Institute of Modern Biology, Nanjing University, Nanjing, China.
  • 4 Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China. xiao.hu@pumcderm.cams.cn.
  • 5 Key Laboratory of Basic and Translational Research on Immune-Mediated Skin Diseases, Chinese Academy of Medical Sciences, Nanjing, China. xiao.hu@pumcderm.cams.cn.
PMID: 40419522 DOI: 10.1038/s41598-025-00586-2
Abstract

While calorie restriction has been suggested to reduce tumor incidence and slow tumor progression through promoting anti-tumor immune response, evidence disclosing how absence of specific nutrient component and alterations of its related metabolic pathways contribute to the process of anti-tumor immune response is still vague. Using human HLA-A*02:01 restricted New York esophageal squamous cell carcinoma-1 (NY-ESO-1) T cell receptor-engineered T (TCR-T) cells as a tool to investigate the impact from nutrient factors on tumor cells for targeted cytotoxicity, we serum-starved both human and murine melanoma cells and monitored their responses to TCR-T cell killing. Serum starvation sensitizes melanoma cells predominantly by reducing Cholesterol availability without causing unwanted off-target effect, as supplementation of Cholesterol compromises the sensitization toward TCR-T cell killing. In response to serum starvation, tumor cells upregulate Cholesterol biogenesis pathways as a compensatory mechanism. Our study reveals the critical role of Cholesterol reduction in mediating serum starvation-induced enhancement of anti-tumor immune response, highlighting the importance of plasma membrane composition in determining tumor cell response to TCR-T cell killing.

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