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. 2022 Nov 2;13(4):1488–1497. doi: 10.1016/j.apsb.2022.10.027

Figure 2.

Figure 2

Lipids reshape tumor microenvironment. Lipids mainly regulate cancer cells, immune cells, and cytokines to form an immunosuppressive tumor microenvironment, which inhibits the immune response and promotes tumor immune evasion. In cancer cell plasma membranes, cholesterol binds to glycosphingolipids, a kind of TAA, to change their conformation so that they cannot be recognized. Moreover, FAO-derived acetyl-CoA upregulates CD47 transcription in glioblastoma multiforme to weaken macrophage phagocytosis. FASN stabilizes the PD-L1 protein by promoting PD-L1 palmitoylation. In DCs, saturated palmitic acid significantly reduces MHC I expression and lowers the conjugation of APCs and T cells and SCFA reduces the expression of costimulatory molecules CD80 and CD86 on DCs and ICOS on T cells during anti-CTLA4 treatment. Increased FA uptake reduces the ability of DCs to process and present antigens and increases the expression of PD-L1. PGE2 reduces the accumulation of TIDCs, which inhibits antigen uptake. In MDSCs, FATP2 promotes the production of PGE2, which causes the expansion of polymorphonuclear MDSCs and further suppression of the antigen-specific T-cell response. Moreover, FATP2-induced lipid accumulation generates ROS and promotes the immunosuppressive effects of MDSCs on T cells. FAO promotes the immunosuppressive function of tumor-infiltrating MDSCs. In T cells, cholesterol increases immune checkpoint expression (e.g., PD-1, 2B4, TIM-3, and LAG-3) and regulates TCR signaling. PGE2 inhibits T-cell proliferation and decreases IL-2 receptor expression in T cells to inhibit the early step of T-cell activation. In regulatory T cells, de novo fatty-acid synthesis mediated by FASN contributes to the functional maturation of Tregs, and COX-2 expression levels are positively correlated with the levels of tumor-infiltrating Foxp3+ Tregs. In macrophages, cholesterol and PGE2 induce macrophages to polarize to M2 TAM. For cytokines secreted by immune cells, lipids not only promote the secretion of immunosuppressive cytokines, such as IL-10 and TGF-β, but also inhibit the secretion of cytotoxic cytokines, such as TNF-α, IFN-γ, and granzyme B. Abbreviations: TAA, tumor-associated antigen; FAO, fatty acid oxidation; PD-L1, programmed cell death ligand 1; DC, dendritic cell; TIDC, tumor-infiltrating dendritic cell; Treg, regulatory T cell; MHC I, major histocompatibility complex class I; APC, antigen presenting cell; SCFA, short-chain fatty acid; ICOS, inducible co-stimulator; CTLA4, cytotoxic T lymphocyte antigen 4; FA, fatty acid; PGE2, prostaglandin E2; MDSCs, myeloid-derived suppressor cells; FATP2, fatty acid transport protein 2; PD-1, programmed cell death 1; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; LAG-3, lymphocyte activation gene-3; IL-2, interleukin-2; IL-10, interleukin-10; TNF-α, tumor necrosis factor α; TGF-β, transforming growth factor-β; FASN, fatty-acid synthase; TCR, T-cell receptor; M1 TAM, M1 tumor-associated macrophage; M2 TAM, M2 tumor-associated macrophage; COX-2, cyclooxygenase-2; IFN-γ, interferon-γ; TME, tumor microenvironment; CoA, coenzyme-A.