Immunotherapy has revolutionized the area of cancer treatment. Although most immunotherapies now are antibodies targeting membrane checkpoint molecules, there is an increasing demand for small-molecule drugs that address intracellular pathways. The E3 ubiquitin ligase Casitas B cell lymphoma‑b (Cbl-b) has been regarded as a promising intracellular immunotherapy target. Cbl-b regulates the downstream proteins of multiple membrane receptors and co-receptors, restricting the activation of the innate and adaptive immune system. Recently, Cbl-b inhibitors have been reported with promising effects on immune surveillance activation and anti-tumor efficacy. Several molecules have entered phase Ⅰ clinical trials. In this review, the biological rationale of Cbl-b as a promising target for cancer immunotherapy and the latest research progress of Cbl-b are summarized, with special emphasis on the allosteric small-molecule inhibitors of Cbl-b.

中文翻译：

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Casitas b 细胞淋巴瘤 B (Cbl-b)：小分子免疫疗法的新治疗途径

免疫疗法彻底改变了癌症治疗领域。尽管现在大多数免疫疗法都是针对膜检查点分子的抗体，但对解决细胞内途径的小分子药物的需求不断增加。 E3 泛素连接酶 Casitas B 细胞淋巴瘤-b (Cbl-b) 被认为是有前途的细胞内免疫治疗靶点。 Cbl-b 调节多个膜受体和辅助受体的下游蛋白，限制先天性和适应性免疫系统的激活。最近，据报道 Cbl-b 抑制剂对免疫监视激活和抗肿瘤功效具有良好的效果。多个分子已进入Ⅰ期临床试验。本文综述了Cbl-b作为癌症免疫治疗有前景的靶点的生物学原理以及Cbl-b的最新研究进展，特别重点介绍了Cbl-b的变构小分子抑制剂。