Figure 2.

The impact of the Warburg effect on the tumor microenvironment. Tumor microenvironment (TME) is composed of different cell types, including tumor, stromal, and immune cells. Increased lactate secretion and acidification remodel these TME populations in favor of tumor progression, angiogenesis, and immunosuppression. Tumor cells and cancer-associated fibroblasts (CAFs) secrete lactate into the media, which in turn can be used by the tumor to meet energy and intermediate product requirements. This phenomenon is known as the reverse Warburg effect. Lactate and acidosis have been described to modulate the phenotype and functionality of several components of the innate and adaptative immune system, inhibiting the proliferation and cytotoxic activity of T-cells and natural killer (NK) cells as well as reducing the differentiation of dendritic cells. In contrast, regulatory T-cells (Tregs) are less sensitive to high lactate concentrations and can maintain their immunosuppressive role. Furthermore, lactate promotes the polarization of tumor-associated macrophages (TAMs) towards a pro-tumoral phenotype, thereby promoting tumor growth and invasion. (GLUT: glucose transporter; IL6: interleukine-6; INF-y: interferon-gamma; MCT1/4: monocarboxylate transporter 1/4; PD1: programmed cell death protein 1).