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 identified the role of LRBA in antitumor immunity and developed a novel immunotherapy for cancers. Interestingly, LRBA was negatively associated with antitumor immunity in human patients. Using high-throughput screening and subsequent structure-based hit optimization, we discovered a small molecule LC427 that bound directly to LRBA, and selectively interfered with the LRBA-CTLA4 interaction. This mechanistically unique LC427 facilitated the lysosomal degradation of CTLA4, and bolstered survival and functions of activated T cells. Importantly, orally administrated LC427 increased tumor-infiltrating CD8+ T cells and displayed effective antitumor activity in tumor-bearing mouse models. Notably, LC427 did not induce typical irAEs observed with immune checkpoint inhibitors in colitis models. Our study demonstrates that targeting LRBA offers a novel and effective strategy with a favorable safety profile, highlighting the potential of LRBA-based immunomodulatory therapies in the treatment of cancers.