Modulating lipid metabolism improves tumor immunotherapy

Abstract

Immunotherapy has progressed significantly in cancer treatment; however, several factors influence its outcomes. Abnormal lipid metabolism, which is frequently observed in cancers, promotes tumor proliferation, invasion, and metastasis. Li et al from the Medical Oncology Department of Chongqing University Cancer Hospital constructed a lipid metabolism scoring system and reported that MK1775 inhibited fatty acid oxidation in tumor-associated macrophages and reduced T-cell infiltration, further enhancing the efficacy of immunotherapy. This study demonstrated the critical role of lipid metabolism scoring system and lipid metabolism in immunotherapy. Currently, the metabolism of lipids, such as fatty acids, phospholipids, and cholesterol, has been reported to affect the tumor microenvironment by regulating immune cells, including T cells, natural killer cells, and macrophages. These metabolic changes can impair the efficacy of immunotherapy, resulting in tumor progression. Consequently, lipid metabolism emerges as an important immune regulator for improving immunotherapeutic outcomes and provides a novel and powerful strategy for tumor combination therapy.

Keywords: Immunotherapy.

Figure 1. Intervention of lipid metabolism to improve immunotherapy. Fatty acid metabolism plays a pivotal role in enhancing the antitumor function of T cells. The exogenous addition of fatty acids, including short-chain fatty acids and linoleic acid, or the reduction of LCFA can bolster the antitumor function of T cells. Inhibiting the expression of CPT1A in tumor cells promotes ferroptosis. The inhibition of fatty acid synthase restricts the immunosuppressive effects of Treg. Phospholipid metabolism significantly impacts the function of different cells. Elevating cardiolipin levels or reducing lysophosphatidic acid can enhance the antitumor function of T cells. By targeting specific molecules, such as PLA2G7 in macrophages, PLA2G10 in tumor cells, and CD36 and PLPP1 in T cells, immunotherapy can be further potentiated. Additionally, modulating cholesterol metabolism also plays a crucial role. Downregulating cholesterol in TME or inhibiting ACAT1 in T cells can boost the antitumor function of T cells. Reducing cholesterol levels enhances the functionality of Tc9 cells. ACAT1, Acyl-CoA cholesterol acyltransferase 1; CPT1A, carnitine palmitoyl transferase 1A; LCFA, long-chain fatty acids; PLA2G7, phospholipase A2 group 7; PLA2G10, phospholipase A2 group 10; PLPP1, phospholipid phosphatase 1; Tc9, interleukin (IL)−9-producing cytotoxic T; TME, tumor microenvironment; Treg, regulatory T cell.