Targeting dysregulated lipid metabolism in the tumor microenvironment

Abstract

The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process. Regulation of lipid metabolizing enzymes has been shown to modulate cancer development and to avoid resistance to anticancer drugs in tumors and the TME. Because of this, understanding the metabolic reprogramming associated with oncogenic progression is important to develop strategies for cancer treatment. Recent advances provide insight into fundamental mechanisms and the connections between altered lipid metabolism and tumorigenesis. In this review, we explore alterations to lipid metabolism and the pivotal factors driving lipid metabolic reprogramming, which exacerbate cancer progression. We also shed light on the latest insights and current therapeutic approaches based on small molecular inhibitors and phytochemicals targeting lipid metabolism for cancer treatment. Further investigations are worthwhile to fully understand the underlying mechanisms and the correlation between altered lipid metabolism and carcinogenesis.

Keywords: Cholesterol transport; Lipid uptake; Lipogenesis; Lipolysis; Phytochemical; Tumor microenvironment.

Fig. 1

Possible regulatory mechanism of lipolysis in tumor microenvironment. Lipolysis is the metabolic process in which triglyceride (TG) is broken down into glycerol and free fatty acids (FA). Overexpression of ATGL and HSL in adipocyte and cancer cells leads to the release of FAs which are used in fatty acid β-oxidation. Adipocyte fatty acid binding protein (FABP4) can bind to long-chain fatty acids reversibly and triggers lipolysis in adipocytes, enabling lipid transfer to cancer cells and promoting β-oxidation. In addition, the interaction of cancer cells with surrounding adipocytes stimulates the secretion of macrophage inhibitory cytokine-1 (MIC-1) and the release of IL-8 by stromal normal fibroblasts, influenced by the fatty acids secreted through activated lipolysis. Exosomal adrenomedullin (ADM) is a multifactorial, hypoxia-inducible peptide facilitates lipolysis through interaction with adipocytes within the tumor microenvironment. The proteins associated with lipolysis highlight the complex interactions between lipid metabolism and the tumor microenvironment, playing a crucial role in the cancer progression, migration, and invasion

Fig. 2

Modulation of lipid metabolism by small molecular inhibitors to treat cancer. Small molecules specifically inhibit their target enzymes involved in lipid metabolism through direct binding and/or suppression of activity (Fatostatin, SREBP inhibitor; Cerulenin, FASN inhibitor; ND-654, ACC inhibitor; SB-204990, ACLY inhibitor). As a consequence, altered lipid modulation remodels TME less favorable for cancer promotion and progression

Fig. 3

Potential multi-target effects of dietary phytochemicals on lipid metabolism in cancer. Unlike small molecular inhibitors, dietary phytochemicals simultaneously modulate multiple targets involved in lipid metabolism, rather than triggering specific single enzyme. This multi-target approach can influence various aspects of TME, while preventing development of resistance to a single pathway