Immune checkpoint inhibitors (ICIs), including anti-CTLA-4 (
cytotoxic T lymphocyte antigen-4) and anti-PD-1/PD-L1 (programmed death-1/
programmed death-ligand 1), represent a turning point in the
cancer immunotherapy. However, only a minor fraction of patients could derive benefit from such
therapy. Therefore, new strategies targeting additional immune regulatory mechanisms are urgently needed. CD4+Foxp3+ regulatory T cells (Tregs) represent a major cellular mechanism in
cancer immune evasion. There is compelling evidence that
tumor necrosis factor (
TNF) receptor type II (
TNFR2) plays a decisive role in the activation and expansion of Tregs and other types of immunosuppressive cells such as myeloid-derived suppressor cells (MDSCs). Furthermore,
TNFR2 is also expressed by some
tumor cells. Emerging experimental evidence indicates that
TNFR2 may be a therapeutic target to enhance naturally occurring or immunotherapeutic-triggered anti-
tumor immune responses. In this article, we discuss recent advances in the understanding of the mechanistic basis underlying the Treg-boosting effect of
TNFR2. The role of TNFR2-expressing highly suppressive Tregs in tumor immune evasion and their possible contribution to the non-responsiveness to checkpoint treatment are analyzed. Moreover, the role of
TNFR2 expression on
tumor cells and the impact of
TNFR2 signaling on other types of cells that shape the immunological landscape in the tumor microenvironment, such as MDSCs, MSCs, ECs, EPCs, CD8+ CTLs, and NK cells, are also discussed. The reports revealing the effect of TNFR2-targeting pharmacological agents in the experimental
cancer immunotherapy are summarized. We also discuss the potential opportunities and challenges for TNFR2-targeting
immunotherapy.