Cannabinoids in hematologic malignancies: mechanisms and therapeutic potential for overcoming drug resistance.

Li S.; Jian X.; Tang Y.; Wang Z.; Min T.; Yu L.; Jiang B.; He Y. · Frontiers in pharmacology · 2026

**Background & Methods** This is a narrative review examining the molecular mechanisms by which cannabinoids may counteract drug resistance in hematologic malignancies (leukemia, lymphoma, and multiple myeloma). The review synthesizes preclinical evidence across experimental models and evaluates potential cannabinoid-based combination strategies with conventional chemotherapy, targeted therapies, immunotherapies, and radiotherapy. **Key Findings** • Cannabinoids may modulate multiple resistance-associated pathways in hematologic malignancies through endocannabinoid system signaling, including effects on ABC transporter-mediated drug efflux, mitochondrial apoptosis regulation, redox homeostasis, endoplasmic reticulum stress, and autophagy modulation. • Preclinical evidence (in vitro and animal studies) demonstrates that cannabinoids may reverse resistant phenotypes and enhance activity of existing treatments; however, these findings are predominantly derived from cell-line and xenograft models with limited translational applicability. • Multiple barriers to clinical translation exist, including pharmacokinetic constraints, potential drug-drug interactions, context-dependent immunological effects that may be neutral or adverse, and the current absence of clinical evidence for antitumor efficacy at pharmacologically achievable exposures. **Dosage & Administration** Not reported. This review does not provide specific dosing recommendations, as clinical evidence for cannabinoid use in hematologic malignancies is insufficient. **Safety & Adverse Effects** Not systematically reported. The review notes that cannabinoid effects may be context-dependent and potentially adverse in certain immunological settings, but does not detail specific safety profiles or adverse event data from clinical studies. **Evidence Quality** This narrative review is limited by its reliance on predominantly preclinical data from cell-line and xenograft models, which have questionable translational relevance to human disease. Critical limitations include: (1) paucity of clinical evidence for antitumor efficacy, (2) lack of studies in immunocompetent models, (3) absence of identified predictive biomarkers for patient selection, (4) insufficient pharmacokinetic characterization at clinically achievable exposures, and (5) lack of prospective clinical trials. The fragmented evidence across disease entities and mechanistic frameworks further limits the ability to draw definitive conclusions. The authors conclude that clinical translation requires validation in immunocompetent and clinically relevant models with rigorous prospective clinical study design before cannabinoids can be recommended for therapeutic use in resistant hematologic malignancies.

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