Cancer cell and macrophage cross-talk in the tumor microenvironment

•The tumor microenvironment contains innate immune cells, for example, macrophages.•Hypoxia imposes stress to tumor cells and their environment.•Tumor cell alter their intermediary metabolism and communication with macrophages.•The mode of tumor cell death dictates the macrophage phenotype. Tumors are composed of tumor cells, nonmalignant cells, and the vascular system. Among them is intense communication via cell–cell contact-dependent mechanisms and/or soluble messengers. In the tumor microenvironment cells often face a certain degree of oxygen and nutrient deprivation. Hypoxic stress alters the metabolism of tumor cells but also of macrophages, as one dominating immune cell population in most solid tumors, with subsequent changes in the microenvironment. This alters the phenotype and metabolism of macrophages, to induce a tumor-promoting reprogramming. Nutrient stress also provokes autophagy to guarantee cell survival or, if overwhelmed, to exit toward cell demise. Death of tumor cells turned out as a communicative system attracting macrophages and directing their phenotype. Depending on the mode of tumor cell death macrophage polarization ranges from the extremes of pro-inflammatory activation toward anti-inflammatory/immuno-suppressive activation. Here we discuss how hypoxia and cell death adds the cross-talk between cancer cells and macrophages.