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Cholesterol metabolism: a new checkpoint in cancer immunity

Lijun Zhao1, Rui Zheng2, Wenyue Liu3

  • 1Henan Key Laboratory of Immunology and Targeted Therapy, Xinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Molecular Immunology and Immunotherapy Laboratory, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan 453003, China; Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.

Trends in Molecular Medicine
|December 10, 2025
PubMed

Insights

Cholesterol metabolism reprogramming drives immunotherapy resistance by altering the tumor microenvironment and suppressing immune cells. Targeting this metabolic-immune checkpoint offers a new strategy to overcome treatment failure.

Area of Science:

  • Oncology
  • Immunology
  • Metabolism

Background:

  • Immunotherapy resistance is a significant clinical hurdle, often driven by the tumor microenvironment.
  • Metabolic reprogramming is increasingly recognized as a key factor contributing to treatment resistance.
  • Cholesterol metabolism plays a central role in modulating the tumor immune landscape.

Purpose of the Study:

  • To review the role of cholesterol metabolism in immunotherapy resistance.
  • To introduce a novel framework conceptualizing cholesterol metabolism as a metabolic-immune checkpoint.
  • To discuss emerging therapeutic strategies targeting cholesterol metabolism to overcome resistance.

Main Methods:

  • Literature review focusing on cholesterol metabolism and immunotherapy resistance.
  • Analysis of the interplay between cholesterol pathways, tumor cells, and immune cells.
  • Synthesis of current research on therapeutic interventions targeting metabolic checkpoints.

Main Results:

  • Dysregulated cholesterol pathways enhance tumor cell survival and immune evasion.
  • Altered cholesterol metabolism suppresses the function of effector immune cells.
  • Cholesterol metabolism acts as a critical metabolic-immune checkpoint influencing treatment response.

Conclusions:

  • Targeting cholesterol metabolism presents a promising strategy to overcome immunotherapy resistance.
  • Understanding cholesterol's role as a metabolic-immune checkpoint can guide novel therapeutic development.
  • Interventions aimed at normalizing cholesterol pathways may restore immune function and improve patient outcomes.
Keywords:
cholesterol metabolismtargeted and combination therapytumor immunitytumor microenvironment

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