Dietary fat and lipid metabolism in the tumor microenvironment

Abstract

Metabolic reprogramming has been considered a core hallmark of cancer, in which excessive accumulation of lipids promote cancer initiation, progression and metastasis. Lipid metabolism often includes the digestion and absorption of dietary fat, and the ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment. Among multiple cancer risk factors, obesity has a positive association with multiple cancer types, while diets like calorie restriction and fasting improve health and delay cancer. Impact of these diets on tumorigenesis or cancer prevention are generally studied on cancer cells, despite heterogeneity of the tumor microenvironment. Cancer cells regularly interact with these heterogeneous microenvironmental components, including immune and stromal cells, to promote cancer progression and metastasis, and there is an intricate metabolic crosstalk between these compartments. Here, we focus on discussing fat metabolism and response to dietary fat in the tumor microenvironment, focusing on both immune and stromal components and shedding light on therapeutic strategies surrounding lipid metabolic and signaling pathways.

Keywords: Fatty acid; High fat diet; Immunosuppression; Lipid metabolism; Obesity; Therapeutic intervention; Tumor microenvironment.

Fig 1.. Overview of tumor-immune-stromal interactions in high fat diet (HFD) induced obesity.

The tumor microenvironment (TME) consists of a complex mixture of cancer cells, immune cells, and stromal cells. In the TME, HFD-induced obesity changes lipid metabolism of different cell populations systematically. Generally, free fatty-acid would accumulate in the TME and become energy supply to the tumor cells. In addition, adipocytes and fibroblasts secrete cytokines that increase inflammation in the TME including IL-1β, IL-6, IL-8, IL-33, and CXCL1. PGE2 will also increase and the pro-inflammatory cytokines will recruit immunosuppressive populations like TAMs, MDSCs and Tregs. Finally, obesity also promotes ECM remodeling in the TME.

Fig 2.. Impact of dietary fat on immune signaling.

As the lipid ingredients increase in the diet, the behavior of the cells in the tumor microenvironment changes in response to changes in signaling cues. Cells with typically anti-tumor responses change into a pro-tumor state. Myeloid cells facilitate tumor progression by providing pro-tumor support, while lymphoid cells help them by not interfering. Tumor-associated macrophage (TAM) pro-tumor functions are amplified through the production of pro-inflammatory mediators, such as PGE2 and IL-1b, and by macrophage Diglyceride acyltransferase (DGAT) mediated TAG synthesis. In MDSCs, leptin is a significant regulator that connects high-fat diet (HFD), chronic inflammation, immune suppression, tumor progression, and metastasis. The infiltration of neutrophils (N) promotes tumor progression and metastasis. On the other hand, excessive lipid accumulation hinders the antigen presentation ability of tumor-infiltrating dendritic cells (DCs). HFD-induced obesity further leads to the depletion of intratumoral CD8+ T cells by decreasing the production of cytokines (IFNγ and TNFα) and granzyme, ultimately hastening tumor growth. Bacterially derived short chain fatty acid (SCFA) levels regulate the gut Treg population, increasing Tregs and decreasing IL-4, IL-23, and IL-17 expression. Overall, obesity has been associated with weakened immune surveillance.

Fig 3.. Impact of dietary fat on stromal cells.

Aggressive tumor cells frequently invade into the adjacent adipose tissue and induce lipolysis in adipocytes. The tumor also dictates the distant adipose tissues to shut down main metabolic processes. Both processes result in FFA release to the TME or excess TAG rich lipoproteins circulating in the host. The unleashed nutrient availability serves to fulfill the highly bioenergetic demands of tumor cells for lipids to be used for proliferation in response to growth stimuli or to survive through metabolic stress. The interaction of CAF and cancer cells lead to metabolic reprogramming in tumors, and reprogrammed CAFs increase several amino acids, lipid and lactate secretions which fuels malignant glucose cancer metabolism, supporting tumor growth. Adipocytes and CAFs also secrete pro-inflammatory cytokines including IL-1β, IL-6, IL-8, IL-33, and CXCL1. They also increase ECM stiffness to regulate tumor metabolism.