The Roles of TNFR2 Signaling in Cancer Cells and the Tumor Microenvironment and the Potency of TNFR2 Targeted Therapy

The appreciation that cancer growth is promoted by a dynamic tumor microenvironment (TME) has spawned novel approaches to cancer treatment. New therapies include agents that activate quiescent T effector cells and agents that interfere with abnormal neovascularity. Although promising, many experimental therapies targeted at the TME have systemic toxicity. Another approach is to target the TME with greater specificity by taking aim at the tumor necrosis factor receptor 2 (TNFR2) signaling pathway. TNFR2 is an attractive molecular target because it is rarely expressed in normal tissues (thus, has low potential for systemic toxicity) and because it is overexpressed on many types of cancer cells as well as on associated TME components, such as T regulatory cells (Tregs), tumor-associated macrophages, and other cells that facilitate tumor progression and spread. Novel therapies that block TNFR2 signaling show promise in cell culture studies, animal models, and human studies. Novel antibodies have been developed that expressly kill only rapidly proliferating cells expressing newly synthesized TNFR2 protein. This review traces the origins of our understanding of TNFR2’s multifaceted roles in the TME and discusses the therapeutic potential of agents designed to block TNFR2 as the cornerstone of a TME-specific strategy.