Accomplices of the Hypoxic Tumor Microenvironment Compromising Antitumor Immunity: Adenosine, Lactate, Acidosis, Vascular Endothelial Growth Factor, Potassium Ions, and Phosphatidylserine

Abstract

In this minireview, we aim to highlight key factors of the tumor microenvironment, including adenosine, lactate, acidosis, vascular endothelial growth factor, phosphatidylserine, high extracellular K⁺ levels, and tumor hypoxia with respect to antitumor immune functions. Most solid tumors have an immature chaotic microvasculature that results in tumor hypoxia. Hypoxia is a key determinant of tumor aggressiveness and therapy resistance and hypoxia-related gene products can thwart antitumor immune responses.

Keywords: acidosis; adenosine; antitumor immunity; lactate; phosphatidylserine; potassium ions; tumor hypoxia; vascular endothelial growth factor.

Figure 1

Adenosine (ADO) concentration measured in experimental tumors (DS-sarcomas, n = 26) as a function of the tissue oxygenation status. With decreasing mean tumor pO₂ values, ADO accumulates in the tumor reaching ~100 µM in severely hypoxic tumors. For comparison, ADO levels in normal tissues are in the range of 10–100 nM (16, 17).

Figure 2

Flow chart describing “classical” hypoxia-/HIF-1α-driven features of the tumor microenvironment (TME) responsible for the local inhibition of antitumor immunity, for tumor progression/recurrence and poor patient outcome (see also list of abbreviations).