Ivermectin as an Investigational Anticancer Agent: Integrative Oncology Perspective San Antonio

A Critical Review of Preclinical Evidence and Emerging Clinical Data

Abstract

Ivermectin, a 16-membered macrocyclic lactone originally developed as an antiparasitic agent, has garnered substantial interest as a potential repurposed anticancer drug. Preclinical studies demonstrate that ivermectin exhibits antitumor activity across numerous cancer cell lines and animal models through multiple mechanistic pathways, including modulation of Wnt/β-catenin, PAK1/Akt/mTOR, and YAP1 signaling; induction of autophagy and apoptosis; targeting of cancer stem cells; reversal of multidrug resistance; and enhancement of immunogenic cell death. Despite this compelling preclinical rationale, clinical evidence in humans remains sparse and preliminary. As of 2025, no large-scale randomized controlled trials have demonstrated survival benefits for ivermectin in any malignancy. Early-phase trials, including a Phase I/II study combining ivermectin with immune checkpoint inhibitors in metastatic triple-negative breast cancer (NCT05318469), are ongoing but have yet to yield mature efficacy data. Healthcare professionals should counsel patients that ivermectin remains an experimental investigational agent in oncology, not a proven cancer therapy, and should discourage unsupervised off-label use while directing interested patients toward registered clinical trials.

Keywords: ivermectin, anticancer, drug repurposing, preclinical, clinical trials, PAK1, Wnt/β-catenin, immunogenic cell death

Introduction

Ivermectin belongs to the avermectin family of compounds, first isolated in 1967 from Streptomyces avermitilis by Drs. Satoshi Ōmura and William Campbell, work that earned them the 2015 Nobel Prize in Physiology or Medicine (Crump & Ōmura, 2011). Approved by the FDA for human use in 1987, ivermectin has since been administered to over 2.7 billion people worldwide for the treatment of parasitic diseases including onchocerciasis (river blindness), lymphatic filariasis, and strongyloidiasis (Laing et al., 2017). Its established safety profile at antiparasitic doses, combined with its low cost and widespread availability, has made ivermectin an attractive candidate for drug repurposing investigations.

In recent years, ivermectin has attracted significant attention in oncology research due to its pleiotropic biological effects that extend beyond antiparasitic activity. Laboratory studies have identified multiple molecular targets through which ivermectin may inhibit tumor growth, metastasis, and angiogenesis (Tang et al., 2021). However, the translation of these preclinical findings to clinical benefit remains unproven. This review critically examines the current evidence for ivermectin’s anticancer properties, emphasizing the distinction between robust preclinical data and the absence of definitive human clinical evidence.

Preclinical Anticancer Evidence

In vitro and in vivo studies have demonstrated that ivermectin inhibits proliferation, induces cell death, and suppresses metastasis across a remarkably broad spectrum of cancer types. These include breast cancer (Dou et al., 2016), colorectal cancer (Jiang et al., 2022; Melotti et al., 2014), gastric cancer (Nambara et al., 2017), hepatocellular carcinoma (Lu et al., 2022), cholangiocarcinoma (Intuyod et al., 2019), renal cell carcinoma (Sharmeen et al., 2010), prostate cancer, leukemias (Wang et al., 2018), gliomas, lung cancers (Nappi et al., 2020), cervical and ovarian cancers (Zhang et al., 2020), nasopharyngeal carcinoma, melanoma (Gallardo et al., 2018), and bladder cancer (Fan et al., 2024).

Reported antitumor effects include decreased cell viability, cell-cycle arrest, reduced clonogenicity, inhibition of tumor growth in xenograft models, and preferential toxicity to cancer cells over normal counterparts at non-cytotoxic doses (Juarez et al., 2020). The median concentration used across in vitro studies is approximately 5 μM (range: 0.01–100 μM), which the authors of a comprehensive review suggest may be clinically achievable based on human pharmacokinetic data (Juarez et al., 2020).

Mechanisms of Action

Preclinical data indicate that ivermectin engages multiple mechanistic axes relevant to tumor biology. The following pathways have been identified as key mediators of its antitumor effects:

PAK1/Akt/mTOR Signaling

P21-activated kinase 1 (PAK1) has emerged as a central node in ivermectin’s anticancer activity. Dou et al. (2016) demonstrated that ivermectin promotes ubiquitination-mediated degradation of PAK1 in breast cancer cells, leading to decreased Akt phosphorylation and blockade of the Akt/mTOR signaling pathway. This mechanism induces cytostatic autophagy—a form of autophagy that inhibits cell proliferation without triggering apoptosis—and suppresses tumor growth in both MCF-7 and MDA-MB-231 breast cancer xenografts. Importantly, ivermectin showed no obvious effects on PAK1 or phosphorylated Akt levels in non-tumorigenic human breast cells, suggesting tumor selectivity.

Wnt/β-Catenin Pathway

Melotti et al. (2014) identified ivermectin as a potent inhibitor of WNT-TCF signaling through a repositioning screen for Wnt pathway blockers. In colorectal cancer cells, ivermectin represses transcription of WNT-TCF target genes including AXIN2, LGR5, and ASCL2, while promoting expression of the Wnt pathway repressor FILIP1L. Mechanistically, Nishio et al. (2022) identified that ivermectin represses Wnt/β-catenin signaling by binding to TELO2, a regulator of phosphatidylinositol 3-kinase-related kinases, leading to downregulation of Axin2, cyclin D1, and β-catenin in DLD-1 colorectal cancer cells. Additionally, Jiang et al. (2022) demonstrated that ivermectin inhibits tumor metastasis by regulating the Wnt/β-catenin/integrin β1/FAK signaling axis in both colorectal and breast cancer models.

YAP1 Inhibition

Yes-associated protein 1 (YAP1) functions as an oncogene through nuclear translocation in multiple malignancies. Nambara et al. (2017) demonstrated that ivermectin suppresses gastric cancer cell proliferation both in vitro and in xenograft models through inhibition of YAP1. The sensitivity to ivermectin correlated with YAP1 expression levels—MKN1 cells with high YAP1 expression were most sensitive (IC50 = 10.2 μM), while MKN7 cells with low YAP1 expression were resistant (IC50 = 31.9 μM). YAP1 knockdown experiments confirmed that the antiproliferative effects were dependent on YAP1 expression.

Programmed Cell Death

Ivermectin induces multiple forms of programmed cell death across various cancer models. Wang et al. (2018) showed that ivermectin selectively induces apoptosis in chronic myeloid leukemia cells through mitochondrial dysfunction and oxidative stress, preferentially targeting cancer cells over normal counterparts. In breast cancer, Draganov et al. (2015) demonstrated that ivermectin modulates P2X4/P2X7/Pannexin-1 signaling to induce a mixed apoptotic and necrotic mode of cell death consistent with pyroptosis, characterized by caspase-1 activation and HMGB1 release. This finding has implications for immunogenic cell death, discussed below.

Cancer Stem Cells and Multidrug Resistance

Ivermectin demonstrates preferential activity against cancer stem cell (CSC)-enriched populations. In triple-negative breast cancer models, ivermectin reduces expression of stemness markers including NANOG, OCT-4, and SOX-2, acting through the PAK1-STAT3 axis (Tang et al., 2021). Additionally, Jiang et al. (2019) demonstrated that ivermectin reverses multidrug resistance (MDR) in vincristine-resistant HCT-8 colorectal cancer cells, doxorubicin-resistant MCF-7 breast cancer cells, and adriamycin-resistant K562 leukemia cells. The mechanism involves inhibition of EGFR and its downstream ERK/Akt/NF-κB signaling cascade, leading to transcriptional downregulation of P-glycoprotein (P-gp)—a key mediator of drug efflux and MDR phenotype. This was the first demonstration of ivermectin’s ability to reverse MDR in vivo using xenograft models.

Tumor Microenvironment and Immunogenic Cell Death

A landmark study by Draganov et al. (2021) published in npj Breast Cancer demonstrated that ivermectin induces immunogenic cell death (ICD) in breast cancer and promotes robust T-cell infiltration into tumors—effectively converting immunologically “cold” tumors to “hot” tumors. The mechanism involves ivermectin’s action as an allosteric modulator of the ATP/P2X4/P2X7/Pannexin-1 axis, enhancing release of damage-associated molecular patterns (DAMPs) including HMGB1 and calreticulin. In 4T1 murine triple-negative breast cancer models, ivermectin selectively targeted immunosuppressive populations including myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), resulting in enhanced effector T cell to Treg ratios. Critically, while neither agent alone showed efficacy in vivo, combination therapy with ivermectin and anti-PD1 antibody achieved synergy in limiting tumor growth (p = 0.03) and promoted complete responses (p < 0.01), including immunity against contralateral re-challenge.

Human Clinical Data and Ongoing Trials

Despite the extensive preclinical evidence, human clinical data for ivermectin in oncology remain limited and early-phase. As of January 2025, no large Phase III randomized controlled trials have demonstrated survival or response-rate benefits for ivermectin in any specific malignancy.

The most notable ongoing clinical effort is a Phase I/II study (NCT05318469) evaluating ivermectin in combination with balstilimab (an anti-PD-1 antibody) or pembrolizumab in patients with metastatic triple-negative breast cancer (mTNBC). Preliminary results presented at the 2025 ASCO Annual Meeting reported on 9 patients enrolled, with a median of 5 prior lines of metastatic therapy (range: 1–7). The combination was well-tolerated; dose levels 1 and 2 were completed with only one serious adverse event attributed to disease-related anemia. Grade 1–3 treatment-related adverse events included maculopapular rash, diarrhea, dysgeusia, generalized muscle weakness, hypothyroidism, and vomiting. Among 8 evaluable patients, 1 achieved a partial response (PR), 1 had stable disease (SD), and 6 had progressive disease (PD). The median progression-free survival was 2.5 months (95% CI: 66 days–not reached), and the 4-month clinical benefit rate was 37.5% (95% CI: 15.3%–91.7%). The authors concluded that the combination is safe and well-tolerated, with encouraging clinical benefit rates warranting continued investigation (Bitar et al., 2025).

It must be emphasized that these are preliminary Phase I dose-finding data with very small patient numbers. The 37.5% clinical benefit rate should be interpreted cautiously given the wide confidence intervals and heavily pretreated population. Overall survival data are not yet mature. The translational gap between robust preclinical efficacy and limited, low-quality clinical evidence remains the central theme of recent oncology reviews (Shah et al., 2025; Garcia-Carrillo et al., 2025).

Dosing, Pharmacology, and Safety Considerations

At standard antiparasitic doses (typically 150–200 μg/kg), ivermectin has an excellent human safety profile with rare serious adverse effects in immunocompetent patients. A Phase I dose-escalation study by Guzzo et al. (2002) demonstrated that ivermectin was generally well tolerated at doses up to 10 times the highest FDA-approved dose (up to 2 mg/kg), with no indication of CNS toxicity as assessed by pupillometry. Adverse events were similar between ivermectin and placebo groups and did not increase with dose.

However, preclinical anticancer effects often occur at concentrations higher than those achieved with standard dosing, raising questions about dose intensity, schedule optimization, and safety in oncology applications. At higher doses, theoretical and observed adverse effects include neurotoxicity (ataxia, confusion, visual disturbances), hepatotoxicity, and drug–drug interactions via P-glycoprotein and cytochrome P450 pathways—particularly relevant in poly-medicated cancer patients (Chandler, 2018).

The current NCT05318469 trial employs oral ivermectin at doses of 30, 45, or 60 mg administered on days 1–3, 8–10, and 15–17 of each 21-day cycle. This intermittent dosing schedule is designed to maximize exposure while allowing drug clearance between cycles. Optimal oncologic dosing, exposure–response relationships, and interaction profiles remain undefined, underscoring the need for controlled trials and careful monitoring.

Ethical and Clinical Communication Considerations

The COVID-19 pandemic and social media amplification have fueled off-label ivermectin use and exaggerated claims of efficacy, including in oncology. A 2025 survey of 30 oncology healthcare practitioners across 20 U.S. cancer institutes found that over 90% had been asked by patients about ivermectin for cancer treatment, with patients typically citing non-scientific online sources (Shah et al., 2025). Case reports have documented toxicity in oncology patients who substituted or added non-prescribed ivermectin to standard regimens, including a pediatric oncology case of ivermectin-induced neurotoxicity in a patient who self-medicated after encountering social media posts (Thompson et al., 2025, preprint).

Expert commentary recommends that clinicians:

1. Clearly distinguish between preclinical promise and the absence of proven clinical benefit, while acknowledging legitimate scientific interest in repurposing.

2. Discourage unsupervised off-label use, especially at supra-therapeutic doses or in combination with hepatotoxic or neurotoxic chemotherapy, instead directing interested patients toward registered clinical trials.

3. Address misinformation empathetically, using understandable explanations of the difference between mechanism and evidence, while reinforcing adherence to therapies with established survival benefit.

4. Maintain open dialogue about alternative therapies patients may be considering, as concealed use can complicate toxicity assessment and treatment monitoring.

Conclusion

Current evidence supports ivermectin as a mechanistically plausible, multipronged anticancer candidate with impressive in vitro and in vivo activity across diverse tumor types. The drug engages multiple oncogenic signaling pathways (PAK1/Akt/mTOR, Wnt/β-catenin, YAP1), induces various forms of programmed cell death, targets cancer stem cells, reverses multidrug resistance, and promotes immunogenic cell death with potential synergy with immune checkpoint inhibitors.

However, the lack of large, well-designed randomized controlled trials means that ivermectin’s clinical value in oncology remains unproven. Healthcare professionals should frame ivermectin as an experimental repurposed agent rather than a proven cancer therapy, and its use should be restricted to ethically conducted clinical studies rather than routine practice. For patients interested in ivermectin, participation in registered clinical trials such as NCT05318469 represents the appropriate pathway forward.

The scientific community should continue rigorous investigation of this affordable, accessible agent while maintaining clear communication with patients about the current state of evidence. The translational gap between compelling preclinical data and absent clinical proof is not unique to ivermectin—it reflects a broader challenge in drug repurposing that demands both scientific humility and continued inquiry.

Author: Dr. Kim

Dr. Yoon Hang "John" Kim is a board-certified integrative medicine physician with over 20 years of clinical experience. He completed his integrative medicine fellowship at the University of Arizona under Dr. Andrew Weil and holds certifications in preventive medicine, medical acupuncture, and integrative/holistic medicine. Through his telemedicine practice, Dr. Kim specializes in using LDN (Low Dose Naltrexone) to treat autoimmune conditions, chronic pain, integrative oncology, and complex conditions, including fibromyalgia, chronic fatigue, MCAS, and mold toxicity. He is the author of three books and more than 20 articles, and has helped establish integrative medicine programs at institutions nationwide.

Professional: www.yoonhangkim.com 

Clinical: www.directintegrativecare.com

Yoon Hang Kim MD Integrative Oncology

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