Letter to the Editor: Fenbendazole liver enzyme elevation in checkpoint inhibitor-treated patients as benzimidazole potentiated immunogenic tumor cell death

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.

Key Words: Fenbendazole; Mebendazole; Benzimidazole; Onconecrosis; Immunogenic cell death; Immune checkpoint inhibitor; Programmed cell death protein-1; Programmed cell death ligand-1; Tumor lysis

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.

TO THE EDITOR

Krishnan et al[1] describing probable fenbendazole-induced liver injury in a 47-year-old woman with metastatic colon cancer on nivolumab/relatlimab [anti-programmed cell death protein-1 (PD-1)/anti-lymphocyte activation gene-3]. We respectfully propose that the biochemical evidence presented may be more compatible with benzimidazole-potentiated immunogenic tumor cell death than with primary drug hepatotoxicity, and that the methodological framework applied is insufficient to support the authors' causal conclusions.

The authors applied the Roussel Uclaf Causality Assessment Method (RUCAM) and scored zero for rechallenge, appropriately acknowledging this gap[2]. Their overall score of 8 (“probable”) rests substantially on the +3 component for improvement after drug cessation — a component that cannot distinguish drug-induced liver injury (DILI) resolution from spontaneous resolution of treatment-induced onconecrosis. We note that RUCAM was designed specifically to assess drug-induced liver injury, and the authors applied it appropriately within that scope; the limitation we describe reflects the instrument's intended purpose rather than an error in the original causality assessment, and does not by itself invalidate the authors’ conclusions.

The authors present immune checkpoint inhibitor (ICI) rechallenge tolerance as their strongest evidence for fenbendazole causality. This logic commits a non-sequitur: Negative ICI rechallenge proves the ICI alone did not cause the injury; it provides no direct evidence that fenbendazole caused it. Under the mechanism we describe below, ICI rechallenge tolerance would also be consistent with this alternative mechanism — not exculpatory proof.

BENZIMIDAZOLES AS ICI POTENTIATORS: THE UNADDRESSED MECHANISM

First, albendazole promotes ubiquitin-mediated proteasomal degradation of programmed death ligand-1 in multiple cancer cell lines and tumor models by suppressing ubiquilin-4 expression[3]. Second, flubendazole downregulates PD-1 through signal transducer and activator of transcription-3 inhibition[4]. Third, mebendazole has been directly tested in synergistic combination with anti-PD-1 in the syngeneic MC38 murine colon carcinoma model — the same cancer type as the reported patient — demonstrating combination-specific suppression of tumor propagation beyond either agent alone[5].

Yuan et al[6] presented Phase I/II results of ivermectin with balstilimab (anti-PD-1) in metastatic triple-negative breast cancer at the 2025 American Society of Clinical Oncology Annual Meeting, demonstrating safety and a 4-month clinical benefit rate of 37.5% in heavily pretreated patients. A Phase II randomized trial (ICONIC, NCT07487805) is enrolling patients with solid tumors to receive ivermectin with immune checkpoint inhibitors, with results expected in 2027. The shared mechanism — antiparasitic drug-induced immunogenic cell death potentiating checkpoint blockade — is directly applicable to benzimidazoles.

IMMUNOGENIC CELL DEATH IN HEPATIC METASTASES

Benzimidazoles generate these signals through microtubule disruption, mitochondrial depolarization, reactive oxygen species generation, and endoplasmic reticulum stress. In a patient with hepatic metastases receiving concurrent PD-1/Lymphocyte activation gene-3 blockade, benzimidazole dose escalation would be expected to produce a wave of immunogenic cell death (ICD) in hepatic tumor deposits, generating: T cell infiltration potentiated by checkpoint blockade; cytokine release and periportal inflammatory edema; and intracellular enzyme release from lysing tumor cells into the portal circulation[7].

The computed tomography scan in the reported case showed “possibly slightly increased mild periportal edema, perihepatic and bilateral subdiaphragmatic implants, and scattered lymphadenopathy”. These findings — periportal edema in a patient with hepatic metastases who had just dose-escalated a benzimidazole ICD inducer on a background of checkpoint inhibition — are compatible with, though not diagnostic of, active hepatic tumor immune response, and in our view warranted more than the single sentence they received.

BIOCHEMICAL PATTERN ANALYSIS

The aspartate aminotransferase (AST): Alanine aminotransferase (ALT) ratio at peak injury in the reported case was 1.01 (AST 2435 U/L, ALT 2407 U/L). Drug-induced hepatocellular injury characteristically produces ALT substantially greater than AST (ALT-dominant pattern, R ratio > 5) because ALT is more liver-specific. Onconecrosis from tumor cell lysis produces AST ≥ ALT because tumor cells contain approximately equal proportions of both enzymes. The histologically confirmed DILI reference case (Thakurdesai et al[8], ALT 2600 U/L, AST 1869 U/L, ratio 0.72) shows the expected ALT-dominant pattern. The Krishnan et al[1] case does not. We acknowledge that the AST: ALT ratio can be influenced by other factors in patients with metastatic cancer, and that this finding is compatible with, rather than diagnostic of, tumor-related onconecrosis.

Additionally, alkaline phosphatase (ALP) was stable at 215 U/L (1.8 × upper limit of normal) throughout the enzyme elevation event. Primary hepatocellular drug injury would not be expected to leave ALP unaffected when transaminases exceed 2400 U/L. The stable ALP is compatible with ongoing tumor-related biliary involvement without new hepatocellular drug injury, though ALP trajectory alone cannot rule out early or mild concurrent drug-related change.

Neither lactate dehydrogenase nor uric acid — the classical tumor lysis markers — was reported. Neither were serial tumor markers (carcinoembryonic antigen, cancer antigen 19-9) before, during, or after the liver injury event. These are the minimum discriminating parameters required to exclude onconecrosis as the primary mechanism.

THE REFERENCE STANDARD: WHAT CONFIRMED DILI LOOKS LIKE

The Thakurdesai case — histologically confirmed severe DILI, ALT-dominant pattern, no active hepatic metastases, no concurrent ICI — remains the most rigorous evidence that fenbendazole can cause genuine human hepatocellular DILI. That case demonstrates what confirmed fenbendazole DILI looks like: Centrilobular necrosis, ALT > AST, complete normalization at three months[8]. The Krishnan et al[1] case differs in every discriminating feature: AST ≈ ALT, active hepatic metastases, concurrent ICI, and periportal edema on computed tomography suggesting immune-mediated tumor response. We note that these differences may partly reflect distinct clinical settings — one patient with active hepatic metastases and concurrent immunotherapy, one without — rather than mutually exclusive mechanisms; the comparison is intended to illustrate possible distinguishing features, not to serve as definitive diagnostic criteria.

MINIMUM STANDARDS FOR FUTURE CASE REPORTS

We propose that future case reports attributing liver injury to fenbendazole in patients with active malignancy receiving concurrent ICI therapy must include: (1) Serial tumor markers before, during, and after the liver injury event; (2) Lactate dehydrogenase and uric acid measured contemporaneously with peak enzyme elevation; (3) Explicit reporting of the AST: ALT ratio; (4) ALP trajectory across the full observation period; (5) Imaging characterization of hepatic tumor deposits for radiological signs of necrosis; (6) Acetaminophen status[9]; and (7) Fenbendazole rechallenge at the pre-escalation dose under monitored conditions — the only experiment that can provide direct evidence for or against drug causality.

Without these elements, RUCAM “probable” in the setting of active hepatic metastases and concurrent ICI therapy is more appropriately classified as “ambiguous — onconecrosis cannot be excluded”.

CONCLUSION

The ICI rechallenge tolerance reported by Krishnan et al[1] is, under the ICD potentiation model, the predicted consequence of removing a benzimidazole ICD inducer from a combination regimen: Restarting the ICI alone does not recapitulate the combination effect. The enzyme elevation they observed may represent the intended therapeutic consequence of a pharmacologically rational drug combination — benzimidazole-induced ICD amplifying checkpoint inhibitor-mediated immune attack on hepatic tumor deposits. Counseling patients to discontinue fenbendazole based on this case, if the ICD potentiation model is correct, may remove an agent whose anticancer potential — not yet demonstrated in clinical trials — warrants further investigation, potentially at the moment of its greatest activity[10]. The patients who are combining these drugs deserve the discriminating investigation that the current literature has not yet provided.