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Review
. 2025 Mar 4;24(3):345-353.
doi: 10.1158/1535-7163.MCT-24-0367.

Vitamin A Metabolism and Resistance of Hepatic Metastases to Immunotherapy

Peter C Jones  1 , Daniel D Von Hoff  2   3
Affiliations
Review

Vitamin A Metabolism and Resistance of Hepatic Metastases to Immunotherapy

Peter C Jones et al. Mol Cancer Ther. .

Abstract

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.

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Conflict of interest statement

P.C. Jones reports being an investor in Agenus, which makes botensilimab and balstilimab mentioned in the article. D.D. Von Hoff reports grants from Agenus during the preparation of this article. D.D. Von Hoff reports stock ownership at Medtronic, CerRx, SynDevRx, UnitedHealthcare, Anthem, Inc., Stromatis Pharma, Systems Oncology, Stingray Therapeutics, Orpheus BioSciences, AADI, Origin Commercial Advisors, Halia Therapeutics, Lycia Therapeutics, and 3+2 Pharma; consulting or advisory role at Imaging Endpoints, Senhwa Biosciences, Alpha Cancer Technologies, CanBas, Lixte Biotechnology, RenovoRx, TD2, Phosplatin Therapeutics, SOTIO, Immunophotonics, Genzada Pharmaceuticals, L.E.A.F Pharmaceuticals, Oncology Ventures, Verily, Athenex, Novita Pharmaceuticals, Vicus Therapeutics, Agenus, Samumed, BioXcel Therapeutics, Sirnaomics, AiMed, Erimos Pharmaceuticals, Pfizer, Axis Therapeutics, ImmuneOncia, Viracta Therapeutics, AlaMab Therapeutics, NeoTX, Xerient, Noxxon Pharma, Reglagene, Lycia Therapeutics, EXACT Therapeutics, ImaginAb, SignaBlok, SonaCare Medical, Caribou Biosciences, Xenter, Compass Therapeutics, Vivacitas Oncology, OnQuality Pharmaceuticals, SELLAS Life Sciences, Catamaran Bio, Thirona Biosciences, Bristol Myers Squibb, Remix Therapeutics, SMP Oncology fka SDP/Tolero, Bessor Pharma, Coordination Pharmaceuticals, Orphagen Pharmaceuticals, Red Arrow Therapeutics, Soley Therapeutics, invIOs GmbH, MEKanistic Therapeutics, POINT Biopharma, Peptomyc, Remunity, SIWA Therapeutics, Xenthera, Indaptus fka Decoy, Panavance Therapeutics fka Geistlich, and CyMon Bio; research funding from Eli Lilly and Company, Genentech, Celgene, Incyte, Merrimack, Plexxikon, Minneamrita Therapeutics, AbbVie, Aduro Biotech, Cleave Biosciences, CytRx Corporation, Daiichi Sankyo, Deciphera, Endocyte, Exelixis, Five Prime Therapeutics, Gilead Sciences, Merck, Pfizer, Pharmacyclics, Phoenix Biotech, Samumed, Strategia, and Halozyme; and patents/royalties/intellectual property at Intramedullary Catheter, Methods of Human Prostate Cancer, Use of 5,6-Dihydro-5-azacytidine in Treatment of Prostate Cancer, Targeting Site-2 Protease (S2P) for the Treatment of Pancreatic Cancer (pending), Targeting Ecto-5-nucleotidase (Cd73) for the Treatment of Pancreatic Cancer, Targeting a Protein Tyrosine Phosphotase-PRL-1 for the Treatment of Pancreatic Cancer (pending), Targeting a Protein PRC1 for the Treatment of Pancreatic Cancer (pending), Targeting Ecto-5-nucleotidase (CD73) for the Treatment of Pancreatic Cancer (pending), Protein Kinase Inhibitors (pending), Methods, Compounds and Compositions with Genotype Selective Anticancer Activity (pending), Methods and Kits to Predict Therapeutic Outcome of BTK Inhibitors (pending), Muscle Fatigue Substance Cytokines and Methods of Inhibiting Tumor Growth Therewith (pending), and 2-Aryl-pyridylazoles for the Treatment of Solid Tumors such as Pancreatic Cancer (pending).

Figures

Figure 1.
Figure 1.
Summary of mechanisms (included in the text) of hypothesized RA contribution to hepatic immune tolerance, generating tumor resistance to checkpoint blockade, along with hypothesized mitigation by disulfiram. Disulfiram suppresses RA generation by HSC in the peritumoral space and within the tumor (through inhibition of ALDH-1—not depicted). For CD4 cells, RA in high concentration inhibits Th1 and Th17 differentiation and promotes Treg generation in the presence of TGFβ generated by the tumor and HSCs. RA also promotes differentiation of monocytes to tumor-associated macrophages, which may kill T cells through Fas/FasL interaction in the liver. RA also induces the purinergic receptor P2X7 in CD8 and CD4 T cells and sensitizes the cells to ATP killing, which is released by tumor cells. RA can also induce terminal exhaustion and apoptosis of activated Teff cells. Tregs travel to distant sites to induce systemic tolerance to tumor antigens and distant metastases, in addition to systemic tolerance generated from antitumor T-cell clonal depletion through the mechanisms depicted.
Figure 2.
Figure 2.
Vit A (retinol) and its precursor and metabolites: β-carotene (provitamin A) from plant sources is converted to retinal which can be either reduced to retinol (reversible) or oxidized to retinoic acid (irreversible).
Figure 3.
Figure 3.
Disulfiram and active metabolites. DDC, diethyldithiocarbamate.
See this image and copyright information in PMC

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