Jones Peter C, Von Hoff Daniel D
Saint John's Cancer Institute, Santa Monica, California.
HonorHealth Research Institute (HHRI), Scottsdale, Arizona.
Mol Cancer Ther. 2025 Mar 4;24(3):345-353. doi: 10.1158/1535-7163.MCT-24-0367.
The liver is an immune-tolerant organ, allowing for organ transplantation with less immune suppression compared with other organs. It also provides fertile soil for tumor metastases, which tend to be more resistant to checkpoint blockade immunotherapy than metastases in other organs. This resistance may result from the sum of incremental evolutionary adaptions in various cell types to prevent overaction to antigens absorbed from the gut into the portal circulation or it might involve a central mechanism. Here, we propose that metabolism of vitamin A, which is highly concentrated in the liver, is a root source of tolerance and resistance of hepatic metastases to checkpoint blockade. Suppression of retinoic acid synthesis from vitamin A with disulfiram may mitigate tolerance and produce enhanced immunotherapy treatment results for patients with liver metastases.
肝脏是一个免疫耐受器官，与其他器官相比，其器官移植所需的免疫抑制较少。它也为肿瘤转移提供了肥沃的土壤，肝脏转移瘤往往比其他器官的转移瘤对检查点阻断免疫疗法更具抗性。这种抗性可能是各种细胞类型中渐进性进化适应的总和，以防止对从肠道吸收进入门静脉循环的抗原过度反应，或者可能涉及一种核心机制。在此，我们提出，高度集中在肝脏中的维生素A代谢是肝转移瘤对检查点阻断产生耐受性和抗性的根源。用双硫仑抑制维生素A合成视黄酸可能会减轻耐受性，并为肝转移患者带来增强的免疫治疗效果。
