Supple W. Letter to the Editor: Fenbendazole liver enzyme elevation in checkpoint inhibitor-treated patients as benzimidazole potentiated immunogenic tumor cell death. World J Clin Cases 2026; 14(25): 124046 [DOI: 10.12998/wjcc.124046]
Corresponding Author of This Article
William Supple, Founder, Principal Investigator, Professor Emeritus, Department of Translational Oncology, Ben Fen Institute, Pierson Drive, Shelburne, VT 05482, United States. bill@benfeninstitute.org
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Oncology
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letter
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Supple W. Letter to the Editor: Fenbendazole liver enzyme elevation in checkpoint inhibitor-treated patients as benzimidazole potentiated immunogenic tumor cell death. World J Clin Cases 2026; 14(25): 124046 [DOI: 10.12998/wjcc.124046]
World J Clin Cases. Sep 6, 2026; 14(25): 124046 Published online Sep 6, 2026. doi: 10.12998/wjcc.124046
Letter to the Editor: Fenbendazole liver enzyme elevation in checkpoint inhibitor-treated patients as benzimidazole potentiated immunogenic tumor cell death
William Supple
William Supple, Department of Translational Oncology, Ben Fen Institute, Shelburne, VT 05482, United States
Author contributions: Supple WF contributed to conceptualization, literature review, data analysis, and preparation of the manuscript; Supple WF has read and approves the final manuscript.
AI contribution statement: None.
Conflict-of-interest statement: This manuscript has not been submitted to, is not under review at, and has not been published in any other journal. The work described has not been published previously in any form. I am the sole author and accept full responsibility for the content of this submission. I have read and agree to the World Journal of Clinical Cases editorial policies, publication ethics guidelines, and the Baishideng Publishing Group Copyright License Agreement terms. No external funding was received for this work. I declare the following potential conflict of interest for full transparency: I am the author of Cancer Is a Parasite: Kill It with the Safe, Over-the-Counter Antiparasitic Fenbendazole (Skyhorse/MAHA Books, 2026). I have no financial relationship with any manufacturer of fenbendazole, mebendazole, or any immune checkpoint inhibitor, and I receive no commercial benefit from the publication of this correspondence. Patient RT, referenced in the observational data presented in the manuscript, provided consent for the use of anonymized serial laboratory data in research publications. All identifying information has been protected by use of a two-letter identifier.
Corresponding author: William Supple, Founder, Principal Investigator, Professor Emeritus, Department of Translational Oncology, Ben Fen Institute, Pierson Drive, Shelburne, VT 05482, United States. bill@benfeninstitute.org
Received: June 4, 2026 Revised: August 18, 2026 Accepted: August 28, 2026 Published online: September 6, 2026 Processing time: 91 Days and 5.7 Hours
Abstract
Krishnan et al published in the World Journal of Clinical Cases report a case of probable fenbendazole-induced liver injury in a patient with metastatic colon cancer on nivolumab/relatlimab, concluding that fenbendazole caused the hepatotoxicity and recommending against its use in cancer patients receiving immune checkpoint inhibitor (ICI). We argue that the biochemical evidence presented is more consistent with immunogenic tumor cell death potentiated by benzimidazole-checkpoint inhibitor synergy than with primary drug hepatotoxicity. Three published mechanisms support this interpretation: Albendazole promotes ubiquitin-mediated proteasomal degradation of programmed cell death ligand-1 via ubiquilin-4 suppression; flubendazole downregulates programmed cell death protein-1 through signal transducer and activator of transcription-3 inhibition; and mebendazole demonstrates direct synergy with anti-programmed cell death protein-1 in syngeneic murine colorectal cancer models. The aspartate aminotransferase: Alanine aminotransferase ratio of 1.01 at peak injury in the reported case, the stable alkaline phosphatase, and the documented hepatic metastases with periportal edema on computed tomography may be more compatible with tumor cell onconecrosis than hepatocellular drug injury, though these findings do not exclude drug-induced injury. The ICI rechallenge result presented as key evidence for fenbendazole causality would also be consistent, under the immunogenic cell death potentiation model, with removal of the inducer — a hypothesis-generating alternative, not proof of isolated drug toxicity. We propose minimum methodological standards for future case reports and a diagnostic framework distinguishing drug-induced liver injury from onconecrosis in benzimidazole-treated cancer patients.
Core Tip: Benzimidazole anthelmintics directly modulate the programmed cell death protein-1/programmed cell death ligand-1 checkpoint axis and induce immunogenic tumor cell death. In cancer patients with hepatic metastases receiving concurrent immune checkpoint inhibitor (ICI), dose-escalation of fenbendazole would be expected to produce a wave of immunogenic tumor cell lysis releasing hepatic enzymes — biochemically indistinguishable from drug hepatotoxicity by currently applied metrics. The aspartate aminotransferase: Alanine aminotransferase ratio, alkaline phosphatase trajectory, lactate dehydrogenase, uric acid, and serial tumor markers are the minimum discriminating parameters required. ICI rechallenge tolerance does not prove fenbendazole causality.
