Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, United States of America; Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
Department of Physiology, Michigan State University, East Lansing, MI, United States of America.
Pharmacol Ther. 2023 Dec;252:108561. doi: 10.1016/j.pharmthera.2023.108561. Epub 2023 Nov 10.
Upon heterodimerizing with other nuclear receptors, retinoid X receptors (RXR) act as ligand-dependent transcription factors, regulating transcription of critical signaling pathways that impact numerous hallmarks of cancer. By controlling both inflammation and immune responses, ligands that activate RXR can modulate the tumor microenvironment. Several small molecule agonists of these essential receptors have been synthesized. Historically, RXR agonists were tested for inhibition of growth in cancer cells, but more recent drug discovery programs screen new molecules for inhibition of inflammation or activation of immune cells. Bexarotene is the first successful example of an effective therapeutic that molecularly targets RXR; this drug was approved to treat cutaneous T cell lymphoma and is still used as a standard of care treatment for this disease. No additional RXR agonists have yet achieved FDA approval, but several promising novel compounds are being developed. In this review, we provide an overview of the multiple mechanisms by which RXR signaling regulates inflammation and tumor immunity. We also discuss the potential of RXR-dependent immune cell modulation for the treatment or prevention of cancer and concomitant challenges and opportunities.
与其他核受体形成异二聚体后，维甲酸 X 受体 (RXR) 作为配体依赖性转录因子发挥作用，调节影响癌症众多特征的关键信号通路的转录。通过控制炎症和免疫反应，激活 RXR 的配体可以调节肿瘤微环境。已经合成了这些必需受体的几种小分子激动剂。从历史上看，RXR 激动剂曾被测试用于抑制癌细胞的生长，但最近的药物发现计划筛选新的分子以抑制炎症或激活免疫细胞。贝沙罗汀是第一个成功的有效治疗药物的例子，该药物通过分子靶向 RXR；该药物已被批准用于治疗皮肤 T 细胞淋巴瘤，目前仍被用作该疾病的标准治疗方法。尚未有其他 RXR 激动剂获得 FDA 批准，但正在开发几种有前途的新型化合物。在这篇综述中，我们概述了 RXR 信号调节炎症和肿瘤免疫的多种机制。我们还讨论了依赖 RXR 的免疫细胞调节在癌症治疗或预防以及伴随的挑战和机遇中的潜在作用。
