The lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency causes severe autoimmune diseases and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) loss in humans. However, the impact of LRBA on antitumor immunity remains understudied. Here we show the important role of LRBA in antitumor immunity and develop small molecules targeting LRBA for cancer immunotherapy. Interestingly, LRBA is negatively associated with antitumor immunity in human patients and mouse models. Using high-throughput screening and subsequent hit optimization, we discover a small molecule LC427 that facilitates the lysosomal degradation of CTLA4 and bolsters survival of activated T cells by binding directly to LRBA and inhibiting the LRBA-CTLA4 interaction. Orally administrated LC427 increases tumor-infiltrating CD8⁺ T cells and displays effective antitumor activity in multiple mouse tumor models. Notably, LC427 does not induce immune-related adverse events observed with immune checkpoint inhibitors in colitis models. Our study demonstrates that targeting LRBA offers an effective strategy for cancer immunotherapy.