E3 ubiquitin-protein ligase CBL-B (CBLB) (CBLB)

E3 ubiquitin-protein ligase CBL-B (Casitas B-lineage lymphoma proto-oncogene b) is a RING-type E3 ubiquitin ligase that serves as a critical intracellular immune checkpoint by negatively regulating the activation of T cells and natural killer (NK) cells [UniProt, 2024; NIH, 2024]. It functions by ubiquitinating key signaling proteins downstream of the T-cell receptor (TCR) and co-stimulatory molecules like CD28, such as Vav1, PI3K, and Zap70, leading to their proteasomal degradation or functional inactivation [UniProt, 2024; BioRxiv, 2023]. This activity is essential for maintaining peripheral tolerance and preventing autoimmunity by establishing a high threshold for immune cell activation [NIH, 2020; Wikipedia, 2024]. In oncology, Cbl-b is often exploited by the tumor microenvironment to induce T-cell anergy and exhaustion, facilitating tumor evasion from the immune system [Nurix Therapeutics, 2026; BioWorld, 2024]. Consequently, Cbl-b has emerged as a high-priority target in immuno-oncology, with several small-molecule inhibitors currently in Phase 1 clinical trials (e.g., NX-1607, HST-1011) [Nurix Therapeutics, 2025; HotSpot Therapeutics, 2024]. These inhibitors typically employ an intramolecular glue mechanism that stabilizes Cbl-b in an inactive, autoinhibited conformation, thereby releasing the brakes on the immune system to enhance anti-tumor responses [BioRxiv, 2026; HotSpot Therapeutics, 2024].

Other names

Cbl-bCasitas B-lineage lymphoma proto-oncogene bRNF56Nbla00127RING finger protein 56SH3-binding protein CBL-BSignal transduction protein CBL-B

Inhibition of Cbl-b E3 ligase activity to enhance T-cell and NK-cell mediated anti-tumor immunity; intramolecular glue mechanism that stabilizes the inactive conformation of the protein.