CBLB (Cbl proto-oncogene B) is an E3 ubiquitin ligase that functions as a master negative regulator of T cell and B cell activation 1. The protein catalyzes Lys-63-linked ubiquitination of multiple substrates including PIK3R1/p85, VAV1, and PLCG1, thereby suppressing T cell receptor (TCR) signaling and imposing a requirement for CD28 costimulation for T cell proliferation 2. In LAG3-mediated immune checkpoint inhibition, CBLB ubiquitinates LAG3 upon ligand engagement, unleashing its inhibitory signaling function 2. CBLB also regulates B cell responses by promoting SYK ubiquitination and degradation 2. Clinically, CBLB dysregulation contributes to autoimmune disease pathogenesis. Deficiency of CBL and CBLB in CD4+ T cells causes hyper T follicular helper cell responses and systemic lupus erythematosus through impaired BCL6 degradation 3. Conversely, CBLB inhibition presents therapeutic opportunities in cancer immunotherapy. CBLB is upregulated in exhausted CD8+ tumor-infiltrating lymphocytes, and its deletion restores effector function and prevents CAR T cell exhaustion 4. Pharmacological CBLB inhibition via NX-1607 enhances T cell activation through MAPK/ERK pathway signaling and demonstrates antitumor activity in murine lymphoma models 5. These findings position CBLB as a promising immunotherapeutic target for both enhancing anti-tumor immunity and managing immune dysregulation.