- Macrophages

In cancer, macrophages present in the tumor are known as TAM and can represent up to 50% of the tumor mass [130]. ROS can be both beneficial and detrimental for the anti-cancer immune function. Therefore, they may indirectly impact cancer progression by altering cancer immune surveillance [131]. Although macrophages have anti-tumor effects as immune cells, experimental and clinical evidence have revealed that TAM contribute to tumor progression and metastasis. High levels of TAM are associated with weak prognosis and decreased overall survival in various cancers [132–135]. The effect of ROS in TAM polarization toward a M1 or M2 phenotype has been discussed, as several studies showed that ROS can stimulate both activation statuses in TAM [49,50,136,137]. M1 and M2 macrophages are two extremes in a continuum of macrophage functional states, which reflect the different effects that can be observed on tumor cells [138].

O2 •– production promotes M2 polarization through activation of ERK and JNK signaling pathways [49,50]. Moreover, administration of the anti-oxidant BHA blocked TAM infiltration and tumor progression, which suggests a beneficial effect of ROS inhibition in tumor therapy [50]. Indeed, another ROS scavenger, oligo-fucoidan, has been reported to inhibit M2 polarization and TAM infiltration in subcutaneous colorectal tumors [139]. Conversely, Wu et al. demonstrated that increased NOX-dependent ROS production by irradiation of macrophages promotes a pro-inflammatory M1 phenotype that is associated with improved response to radiotherapy in rectal cancer [137]. Similarly, iron overload has been reported to polarize macrophages towards an M1 phenotype by increasing ROS production and reduction in ROS levels by N-Acetyl-Cysteine repressed M1 polarization [136]. These results confirm a link between ROS generation and M1 polarization of macrophages. Apart from polarization, ROS also govern TAM apoptosis. For example, inhibition of autophagy in macrophages increases ROS levels, provokes TAM apoptosis and leads to regression of the primary tumor [140]. TAM are also major players in the regulation of tumor angiogenesis in colorectal cancer [141]. They have been demonstrated to enhance the expression of angiogenic proteins in the tumor microenvironment in an oxidative stress-dependent manner by regulating the activity of NOXs [142].
