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<p>Cholesterol is increasingly recognized as a central coordinator of tumor signaling, metabolism, and immune evasion. In addition to their structural role in membranes, cholesterol-enriched lipid rafts stabilize oncogenic pathways such as those involving EGFR, Src, and ERRα, promoting cancer stemness and therapeutic resistance. Excess cholesterol within mitochondria reduces membrane permeability, prevents cytochrome c release, and contributes to resistance to apoptosis. Moreover, cholesterol-derived oxysterols reshape the tumor microenvironment by inducing Th17 polarization, XBP1-dependent CD8⁺ T-cell exhaustion, and macrophage M2 reprogramming. These interconnected mechanisms reveal that cholesterol is a metabolic hub linking intracellular survival pathways with immune dysfunction. Pharmacologic and dietary modulators: Statin, ezetimibe, and ω-3 fatty acids can remodel cholesterol pools, reverse raft stabilization, and partially restore sensitivity to targeted or immune therapies in preclinical models. Recognizing cholesterol metabolism as a contributing factor to oncogenic signaling and immune suppression highlights potential theoretical avenues for biomarker-guided treatment combinations. This integrative framework positions cholesterol not only as a structural lipid but also as a dynamic regulator of tumor evolution and therapy response.</p>

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Cholesterol as a metabolic integrator of oncogenic signaling, immune evasion, and therapy resistance

  • 期刊论文

  • 发表日期：

    2026年5月29日

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  • Vladislav Skossyrskiy,
  • Evgeniy Prozorenko,
  • Igor Gadaev,
  • Andrey Skossyrskiy,
  • Ekaterina Orlova,
  • Marina Sekacheva

摘要

Cholesterol is increasingly recognized as a central coordinator of tumor signaling, metabolism, and immune evasion. In addition to their structural role in membranes, cholesterol-enriched lipid rafts stabilize oncogenic pathways such as those involving EGFR, Src, and ERRα, promoting cancer stemness and therapeutic resistance. Excess cholesterol within mitochondria reduces membrane permeability, prevents cytochrome c release, and contributes to resistance to apoptosis. Moreover, cholesterol-derived oxysterols reshape the tumor microenvironment by inducing Th17 polarization, XBP1-dependent CD8⁺ T-cell exhaustion, and macrophage M2 reprogramming. These interconnected mechanisms reveal that cholesterol is a metabolic hub linking intracellular survival pathways with immune dysfunction. Pharmacologic and dietary modulators: Statin, ezetimibe, and ω-3 fatty acids can remodel cholesterol pools, reverse raft stabilization, and partially restore sensitivity to targeted or immune therapies in preclinical models. Recognizing cholesterol metabolism as a contributing factor to oncogenic signaling and immune suppression highlights potential theoretical avenues for biomarker-guided treatment combinations. This integrative framework positions cholesterol not only as a structural lipid but also as a dynamic regulator of tumor evolution and therapy response.