Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity

Cellular mechanisms linking cancers to obesity

“…Also, these findings suggested that fatty acids activate a mTOR and MAPK dependent signaling network to facilitate increased glycolytic and aerobic respiration in breast cancer cells. Finally, cancer cells and immune cells display distinct metabolic adaptations in the obesogenic tumor microenvironment [ 92 ]. For example, HFD represses PHD3 expression specifically in cancer cells, which rewire their metabolism to accelerate fatty acid uptake and oxidation.…”

“…For example, HFD represses PHD3 expression specifically in cancer cells, which rewire their metabolism to accelerate fatty acid uptake and oxidation. This in turn impacts the fatty acid availability for T cells in the same microenvironment and thereby impairs T cells infiltration and function [ 92 ].…”

“…Tumoral T cell function is of great interest, especially since the T cell is the critical mediator of immunotherapies, including adoptive T cell therapy and immune checkpoint therapy. Obese cancer patients have been reported to display increased levels of dysfunctional and exhausted T cells [ 92 , 109 ], suggesting that immunotherapy could be a promising treatment option for obese cancer patients. Indeed, in both human patients and preclinical animal models, obesity associates with better response to anti-PD1 and anti-CD8 immune checkpoint therapy [ 92 , 109 , 110 ].…”

The Cancer Cell Dissemination Machinery as an Immunosuppressive Niche: A New Obstacle Towards the Era of Cancer Immunotherapy

“…However, it is generally known that fatty acids are primarily required by rapidly dividing tumor cells to form new plasma membrane lipid bilayers, thus explaining why most tumors overexpress FAS and malignant transformation depends on lipogenesis (251). However, neither migratory tumor cells nor effector T cells seem to heavily depend on fatty acid oxidation, although the development of antitumor memory T cells is affected (252)(253)(254), suggesting that such pathways may not be as immunocompromising within the dissemination trajectories. On the other hand, there are certain lines of evidence suggesting that the highly migratory/invasive cells that have undergone EMT tend to express high levels of the glucose transporter GLUT1, which partially supports high energy demands for the active process of invasion and migration (255,256).…”

Pancreatic Tumorigenesis: Oncogenic KRAS and the Vulnerability of the Pancreas to Obesity

“…Similarly, an adipose tissue dysfunctional pro-inflammatory microenvironment may be induced by interaction with local tumor cells and tumor-secreted factors, independent from obesity with both obesity-related and tumor-related mechanisms forming a dysfunctional metabolic milieu [23][24][25]. These mutually reinforcing microenvironmental interactions contribute to (1) derangement of local and systemic glucose, lipid, and energy metabolic homeostasis [26][27][28]; (2) altered secretory functions as well as the local and systemic release of pro-tumorigenic and pro-inflammatory elements, such as growth factors, cytokines, chemokines, hormones, nutritional substrates, and extracellular vesicles [29][30][31][32][33]; (3) induction of stress, such as the endoplasmic reticulum (ER) stress, oxidative stress, and stress-induced tissue damage [34]; (4) activation, expansion, and recruitment of inflammatory and immune cells [35]; (5) alteration of tumor immunity and immune evasion [36,37]; (6) the extracellular matrix (ECM) remodeling, stromal cell activation, accumulation of adipose stem/stromal cells, fibrosis, and desmoplasia [30,38]; (7) stimulation of tumor cell growth, tumor angiogenesis, and lymphangiogenesis [39,40]. Thus, these local and systemic alterations occurring as a result of chronic obesity create an environment fostering the initiation, progression, and invasiveness of cancer, including PDAC.…”