Table Info

Table 1.

Role of cholesterol in TIME

Cell type	Cholesterol role in cancer/HCC	References
Macrophages	Cholesterol induces macrophage recruitment and differentiation to M2 polarity in HCC. HCD induces M1 macrophages in early stages of HCC development, contrarily to M2 polarity in chronic phases. Cholesterol efflux is associated with aggressivity in cancer. HFHCD induce M2 macrophage polarization or CD206⁺ cells. The primary sources of oxysterols such as 27-HC are M2 macrophages.	[5, 28, 45, 47, 52, 59]
Neutrophils	HCD promotes neutrophil infiltration in HCC models. Oxidized cholesterol plays an essential role in neutrophils attracting in a CXCR2-dependent manner. Oxidized cholesterol correlates with tumor aggressivity. NASH-HCC tumors have high neutrophil infiltration.	[47, 58, 60]
NK	Cholesterol promotes NK cell activation and NKG2D, and NCR1 receptors are reflected in aggressivity reduction. Deletion of ApoE (ApoE^−/−) provokes fewer and smaller liver tumors, augmenting effector functions of NK cells. The dysfunctional response of iNKT cells with high lipids and cholesterol biosynthesis in B16F10 is the opposite response in liver tumors.	[63, 64]
DC	Oxidized lipid forms inhibit antigen cross-presentation and peptide MHC class I complexes, reducing anti-tumor strategy. LXR affects DC in a CCR7-dependent mechanism, observing decrement in migration to lymphoid tissues.	[67, 68]
T lymphocytes	T lymphocytes have pleiotropic roles, activating a high variety of subsets of T cells in the NAFLD spectrum and HCC. HCD induces inflammation with T lymphocytes (CD3⁺ CD4⁺ CD8⁺) recruitment in the liver. Cholesterol accumulation in the microenvironment induces immune checkpoint inhibitors (PD-1, 2B4, TIM-3, and LAG-3) in CD8⁺ cells. Cholesterol overload is associated with an increment in Treg.	[72–75]

27-HC: 27-hydroxy-cholesterol; ApoE: apolipoprotein E

Declarations

Author contributions

AEC conceptualized the manuscript, wrote the draft, and revised the final manuscript. LCR and ASN wrote and revised the draft. VSA and RUML provided the input in writing the paper. LEGQ conceptualized the manuscript and revised the draft and the final manuscript. MCGR conceptualized the manuscript, designed the outline, and coordinated the writing and financial support.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was funded by “Universidad Autónoma Metropolitana” and “Conacyt-Fronteras de la Ciencia-1320”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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