The liver is an immune tolerant organ, allowing for organ transplantation with less immune suppression compared to 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.
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