Fig. 5

The “fruit tree” schematic diagram of the metabolic coupling between stromal and cancer cells through nutrients and metabolites. CAFs provide mitochondrial fuels for cancer cells, including lactate, ketone body, fatty acyls, and Gln. TANs can release ROS and RNS to kill cancer cells directly. TECs absorb glucose molecules and then provide them to cancer cells. TAMs are influenced by lactate that is exported from cancer cells, while TAMs provide cancer cells with TGF-β which elevated the glycolytic rate of cancer cells. Malignant B cells tend to be glycolytic and Gln-addicted. Since all cells compete for nutrients of glucose, fatty acid, and amino acid, under this nutrient-deficient TMME, T cells and NK cells are immunosuppressive with less IFNγ releasement. TGF-β-mediated metabolic coupling with cancer cells mainly occurs in T cells based on previous literature. 1. Cancer cells with increased aerobic glycolysis by HK2 expression are easier to “educate” antitumor CD4 + T cell to be immune-suppressed through ways below: Stimulate CD4 + T cell secret TGF-β, an immune-suppressing cytokine; and glucose competition between cancer cells and CD4 + T cells lowers glycolytic rate in CD4 + T cells, which decreases the antitumor activity of CD4 + T cells by IFNγ production decline. 2. Cancer cell-derived TGF-β can also decrease INFγ secretion of CD4+ T cells. Few/abnormal blood vessels lead to a hypoxic TMME(O₂↓) which stimulates aerobic glycolysis in cancer cells and stromal cells. Lactate produced by glycolysis contributes to an acidic TMME(H⁺↑). Since all cells in TMME compete for the restricted nutrient, therefore nutrient is deficient (Nutrient↓) in TMME. CAFs: cancer-associated fibroblasts, Gln: glutamine; Arg: arginine; TAN: tumor-associated neutrophils; ROS: reactive oxygen species; RNS: reactive nitrogen species. TECs: tumor endothelial cells; TAMs: tumor-associated macrophages; Arg: arginine; TMME: tumor metabolic microenvironment; and HK2: Hexokinase 2