Accumulated cholesterol protects tumours from elevated lipid peroxidation in the microenvironment

Area of Science:

• Biochemistry
• Cancer Biology
• Immunology

Background:

• Elevated lipid peroxidation (LPO) in the tumour microenvironment (TME) impacts antitumour immunity.
• Tumour cells can alter metabolism to survive high LPO levels.
• Ferroptosis, a form of cell death, is characterized by LPO accumulation.

Purpose of the Study:

• To investigate a novel, non-antioxidant mechanism by which tumour cells utilize cholesterol to resist LPO and ferroptosis.
• To explore the role of cholesterol metabolism in modulating tumour cell susceptibility to ferroptosis.
• To assess the therapeutic potential of targeting cholesterol metabolism for enhancing ferroptosis-based cancer treatments.

Main Methods:

• Investigated cholesterol metabolism modulation, including LDLR-mediated uptake.
• Assessed the effect of elevated cellular cholesterol on LPO induced by GSH-GPX4 inhibition and oxidizing agents.
• Utilized MβCD to deplete TME cholesterol in a mouse xenograft model.
• Analyzed the relationship between LPO and lipid rafts in tumour tissues.

Main Results:

• Tumour cells accumulate cholesterol to inhibit LPO and ferroptosis.
• Cholesterol accumulation decreases membrane fluidity and promotes lipid raft formation, hindering LPO substrate diffusion.
• Depletion of TME cholesterol with MβCD enhanced ferroptosis efficacy in a mouse model.
• A correlation between LPO and lipid rafts was observed in renal cancer patient tissues.

Conclusions:

• Cholesterol provides a non-antioxidant mechanism for tumour cells to suppress LPO and ferroptosis.
• Modulating cholesterol metabolism, particularly uptake via LDLR, influences ferroptosis sensitivity.
• Targeting cholesterol metabolism offers a strategy to enhance the efficacy of ferroptosis-based antitumour therapies.