Hussein Sara A, Saadawy Ahmed H, Badr Eman, Abdollah Maha R A, Wael Neamtullah, Allam Rasha M, Al-Abd Ahmed M, Roncero Sanchez Ana Maria, Tolba Mai F
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Abbassia, 11566, Cairo, Egypt.
Center for Drug Discovery Research and Development, Ain Shams University, Cairo, Egypt.
Med Oncol. 2025 Aug 26;42(10):447. doi: 10.1007/s12032-025-02996-8.
Given the pivotal role of CDK4/6 deregulation in the pathogenesis of various malignancies, CDK4/6 inhibitors have been incorporated into cancer treatment protocols. Beyond their antiproliferative effects, these inhibitors exhibit prominent immunomodulatory properties. Preclinical data indicated that CDK4/6 inhibitors enhance the tumor cell antigen presentation capacity and restrict the proliferation of immunosuppressive regulatory T-cells. Furthermore, studies showed that CDK4/6 inhibitors could enhance the development of memory T-cell in vivo in melanoma mouse models and in the clinical setting in breast cancer (BC) patients. In silico analysis identified 225 protein targets for CDK4/6 inhibitors involved in 57 immune-related pathways which further supported the immune-modulatory potential of these inhibitors in innate immunity, cytokine signaling, and adaptive immunity. Furthermore, 24 targets exhibited significantly higher protein expression in immune cell types compared to non-immune cell types, as indicated by data from the Human Protein Atlas. The favorable modulation of T-cell immunity by CDK4/6 inhibitors could complement the antitumor effect of immunotherapies, such as immune checkpoint inhibitors (ICIs), which hamper PD-1 /PD-L1 signaling and result in the reactivation of the antitumor T-cell response. Herein, we explore the clinical portfolio of CDK4/6 inhibitors across various solid malignancies, with emphasis on emerging combinations with ICIs.
鉴于细胞周期蛋白依赖性激酶4/6（CDK4/6）失调在各种恶性肿瘤发病机制中的关键作用，CDK4/6抑制剂已被纳入癌症治疗方案。除了其抗增殖作用外，这些抑制剂还具有显著的免疫调节特性。临床前数据表明，CDK4/6抑制剂可增强肿瘤细胞抗原呈递能力，并限制免疫抑制性调节性T细胞的增殖。此外，研究表明，CDK4/6抑制剂可在黑色素瘤小鼠模型的体内以及乳腺癌（BC）患者的临床环境中增强记忆T细胞的发育。计算机分析确定了CDK4/6抑制剂的225个蛋白质靶点，这些靶点参与57条免疫相关途径，进一步支持了这些抑制剂在固有免疫、细胞因子信号传导和适应性免疫中的免疫调节潜力。此外，根据人类蛋白质图谱的数据，与非免疫细胞类型相比，24个靶点在免疫细胞类型中表现出显著更高的蛋白质表达。CDK4/6抑制剂对T细胞免疫的有利调节可补充免疫疗法（如免疫检查点抑制剂（ICI））的抗肿瘤作用，免疫检查点抑制剂可阻碍PD-1/PD-L1信号传导并导致抗肿瘤T细胞反应的重新激活。在此，我们探讨了CDK4/6抑制剂在各种实体恶性肿瘤中的临床应用情况，重点是与ICI的新兴联合应用。
