Which cancers showed the strongest preclinical response to ivermectin and by what mechanisms?
Executive summary
Preclinical work identifies strongest anticancer signals for ivermectin in breast cancer, hematologic malignancies (notably leukemia), hepatocellular carcinoma, and several drug-resistant solid tumor models, with repeated reports of tumor growth inhibition or enhanced chemotherapy efficacy in cell lines and animal models [1] [2] [3] [4]. The proposed mechanisms are multi‑faceted—induction of apoptosis/oxidative stress, inhibition of pro‑survival signaling (Akt/mTOR, STAT3, Wnt/β‑catenin), modulation of ion channels and purinergic receptors, reduction of cancer stemness, and immune microenvironment remodeling—often acting in combination and frequently producing synergy with standard agents in vivo [4] [5] [1] [3].
1. Breast cancer: “Converting cold tumors hot” with immunogenic death
Preclinical models of breast cancer show some of the most compelling and mechanistically rich results: ivermectin induces immunogenic cancer cell death, increases T‑cell infiltration, selectively depletes immunosuppressive myeloid and regulatory T‑cell populations, and synergizes with anti‑PD‑1 checkpoint blockade to produce tumor regressions and durable responses in mouse models [1]. These findings position ivermectin not only as a cytotoxic agent but as an immune‑modulating adjuvant in triple‑negative breast cancer models, where combination therapy produced statistically significant tumor control versus either agent alone in the cited study [1].
2. Leukemia and other hematologic cancers: membrane hyperpolarization, ROS, and synergy with chemo
Hematologic models—especially acute and chronic leukemia cell lines—display robust preclinical sensitivity: ivermectin induces chloride‑dependent membrane hyperpolarization, increases intracellular reactive oxygen species, and triggers caspase‑dependent cell death, with reported synergy when combined with cytarabine or daunorubicin in vitro and in vivo studies [2] [4]. Additional reports describe selective mitochondrial dysfunction and oxidative stress in chronic myeloid leukemia cells and reversal of drug resistance in myeloid leukemia models, supporting a blood‑cancer signal across multiple laboratories [4] [6].
3. Hepatocellular carcinoma, ovarian, lung and drug‑resistant solid tumors: pathway blockade and chemo‑sensitization
Ivermectin shows reproducible preclinical activity against several solid tumors by inhibiting oncogenic signaling and enhancing other drugs: in hepatocellular carcinoma models ivermectin suppresses mTOR/STAT3 signaling and synergizes with sorafenib to inhibit tumor growth in xenografts [3]; in ovarian cancer it sensitizes cells to cisplatin via Akt/mTOR inhibition and demonstrates synergy with paclitaxel in animal experiments [4]. Reports also note enhanced efficacy of EGFR‑targeted agents in lung and colorectal models and reversal of ABCB1‑mediated drug resistance in non‑small cell lung cancer models, highlighting a consistent pattern of chemosensitization and resistance‑reversal [4] [7] [8].
4. Mechanistic landscape: a multitargeted “dirty” drug
Across studies ivermectin acts through a constellation of mechanisms rather than a single target: apoptosis induction through caspase activation and mitochondrial dysfunction, oxidative stress generation, inhibition of Akt/mTOR, STAT3 and Wnt/β‑catenin pathways, modulation of PAK1 and nuclear transport protein KPNB1, interference with RNA helicase‑dependent miRNA processing, direct effects on chloride channels and ATP/P2X4/P2X7 purinergic signaling, and reduction of stemness markers (Nanog/Oct4/Sox2)—all reported in preclinical literature [4] [5] [1] [2] [9]. These multi‑pronged effects help explain observed synergy with chemotherapies, targeted agents, and immune checkpoint inhibitors in animal models [4] [3] [1].
5. Limits, caveats, and where the evidence is weakest
The preclinical package is broad but remains preclinical: most positive findings derive from cell lines and xenografts with limited clinical translation to date, and reviewers repeatedly warn of the translational gap and risks of off‑label use driven by social media rather than controlled trials [10] [11]. Some tumor types, including gynecologic cancers, lack robust safety‑oriented data and formal recommendations cautioning against clinical use outside trials have been published [12]. Early phase clinical testing and careful pharmacokinetic/toxicity work are needed before efficacy claims in humans can be made; ongoing trials combining ivermectin with immunotherapy or targeted therapy are being logged but clinical readouts remain limited [13] [14].