Abstract
A major paradigm in cancer immunotherapy is the use of checkpoint inhibitors to break regulatory mechanisms that usually guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example that helped establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The former is attributable to inactivation of the CTLA-4 checkpoint, while the latter is due to selective depletion of regulatory T cells (Treg) in a tumor microenvironment. Here we argue that for safer and more effective CTLA-4-targeting immune therapy, one should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg depletion in a tumor microenvironment.