Tumor Necrosis Factor Receptor 2 (TNFR2): An Emerging Target in Cancer Therapy

Simple Summary Tumor necrosis factor (TNF) receptor-2 (TNFR2) affects tumor development and metastasis in several ways. TNFR2 promotes tumor immune escape by virtue of its ability to stimulate various immune suppressive cell types, e.g., regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and can act as an oncogene. However, TNFR2 also elicits antitumoral activities by costimulation of cytotoxic T-cells. Accordingly, antagonists and agonists targeting TNFR2 have been preclinically evaluated for tumor therapy and have demonstrated anti-tumor activity in preclinical studies. In this review, we summarize the most important TNFR2-related findings regarding tumor biology and cancer therapy and especially discuss the mode of action of currently used agonists and antagonists of TNFR2. Despite the great success of TNF blockers in the treatment of autoimmune diseases and the identification of TNF as a factor that influences the development of tumors in many ways, the role of TNFR2 in tumor biology and its potential suitability as a therapeutic target in cancer therapy have long been underestimated. This has been fundamentally changed with the identification of TNFR2 as a regulatory T-cell (Treg)-stimulating factor and the general clinical breakthrough of immunotherapeutic approaches. However, considering TNFR2 as a sole immunosuppressive factor in the tumor microenvironment does not go far enough. TNFR2 can also co-stimulate CD8(+) T-cells, sensitize some immune and tumor cells to the cytotoxic effects of TNFR1 and/or acts as an oncogene. In view of the wide range of cancer-associated TNFR2 activities, it is not surprising that both antagonists and agonists of TNFR2 are considered for tumor therapy and have indeed shown overwhelming anti-tumor activity in preclinical studies. Based on a brief summary of TNFR2 signaling and the immunoregulatory functions of TNFR2, we discuss here the main preclinical findings and insights gained with TNFR2 agonists and antagonists. In particular, we address the question of which TNFR2-associated molecular and cellular mechanisms underlie the observed anti-tumoral activities of TNFR2 agonists and antagonists.