Cholesterol metabolism in tumor microenvironment: cancer hallmarks and therapeutic opportunities

Abstract

Cholesterol is crucial for cell survival and growth, and dysregulation of cholesterol homeostasis has been linked to the development of cancer. The tumor microenvironment (TME) facilitates tumor cell survival and growth, and crosstalk between cholesterol metabolism and the TME contributes to tumorigenesis and tumor progression. Targeting cholesterol metabolism has demonstrated significant antitumor effects in preclinical and clinical studies. In this review, we discuss the regulatory mechanisms of cholesterol homeostasis and the impact of its dysregulation on the hallmarks of cancer. We also describe how cholesterol metabolism reprograms the TME across seven specialized microenvironments. Furthermore, we discuss the potential of targeting cholesterol metabolism as a therapeutic strategy for tumors. This approach not only exerts antitumor effects in monotherapy and combination therapy but also mitigates the adverse effects associated with conventional tumor therapy. Finally, we outline the unresolved questions and suggest potential avenues for future investigations on cholesterol metabolism in relation to cancer.

Keywords: antitumor immunity; cholesterol homeostasis; drug repurposing; metastasis; statin; tumor microenvironment.

Figure 1

Regulation of mammalian cholesterol homeostasis. Hepatic cholesterol biosynthesis and dietary cholesterol primary sources of cholesterol in humans. Excess cholesterol in the liver is excreted into the bile and eventually into the intestinal lumen for fecal excretion. Cholesterol in the circulation can be excreted directly into the intestinal lumen via enterocytes. This figure was created using BioRender (https://biorender.com/).

Figure 2

Regulation of cellular cholesterol homeostasis. The maintenance of cholesterol homeostasis is critical for physiological functions. Cellular cholesterol homeostasis is dynamically balanced through various processes, such as biosynthesis, uptake, esterification, efflux, and processing. Intracellular cholesterol levels are precisely regulated by these processes. This figure was created using BioRender (https://biorender.com/).

Figure 3

Dysregulation of cholesterol homeostasis and hallmarks of cancer. Hanahan and Weinberg originally proposed the concept of cancer hallmarks, which has since been expanded to encompass fourteen hallmarks. We summarize the association between dysregulated cholesterol homeostasis and some of these cancer hallmarks, although further exploration is necessary to fully understand this relationship. This figure was created using BioRender (https://biorender.com/).

Figure 4

Crosstalk between cholesterol metabolism and the TME. The TME has been categorized into seven specialized microenvironments: hypoxic niche, immune microenvironment, metabolism microenvironment, acidic niche, innervated niche, mechanical microenvironment, and microbial microenvironment (including intratumor and gut microbiota). Crosstalk between cholesterol metabolism and specialized microenvironments plays a significant role in tumorigenesis and tumor progression. This figure was created using BioRender (https://biorender.com/).