Les Liaisons dangereuses: the paradoxical outcomes of the cytotoxic activity of tumor macrophages

The study of the role of the immune system in tumor progression has been ongoing for over a century, starting with Paul Ehrlich’s hypothesis on its role in limiting the development of oncological diseases. The development of cancer immunology has confirmed this concept and identified mechanisms of complex interactions between immune system cells and both foreign agents and transformed cells within the organism. Macrophages, natural killers, and T-lymphocytes play key roles in destroying tumor cells. Among them, special attention is given to tumor-associated macrophages. Tumor cells can modulate macrophage activity, transforming them into cells with immunosuppressive properties that promote angiogenesis and extracellular matrix remodeling. As a result, the largest population of tumor-associated macrophages consists of cells with an anti-inflammatory/pro-tumor phenotype (M2).Macrophages with an anti-inflammatory phenotype (M1) are characterized by the production of pro-inflammatory cytokines, reactive oxygen species, and strong cytotoxic activity. They can directly or indirectly destroy tumor cells by involving other immune cells. Traditionally, the cytotoxic activity of macrophages is considered an important mechanism in limiting tumor growth, but in some cases, it is insufficient for effective tumor control. Recent data suggest that tumor cells can develop defense mechanisms against macrophage cytotoxicity and acquire the ability to overcome it. Moreover, tumor cells resulting from interaction with cytotoxic macrophages possess other properties that provide growth advantages.This review is dedicated to describing a new pro-tumor function of M1 macrophages, traditionally considered anti-tumor.