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

Hematologic malignancies are highly heterogeneous diseases in which the emergence of therapy resistance remains a major obstacle to durable clinical benefit. Cannabinoids, acting through the endocannabinoid system, have drawn increasing interest because of their potential to modulate multiple resistance-associated pathways, yet the available evidence remains fragmented across disease entities, experimental models, and mechanistic frameworks. In this narrative review, we examine the molecular mechanisms by which cannabinoids may counteract drug resistance in leukemia, lymphoma, and multiple myeloma. We discuss their effects on ABC transporter-mediated drug efflux, mitochondrial apoptosis, redox homeostasis, endoplasmic reticulum stress and autophagy, pro-survival signaling, and tumor microenvironment-mediated protection. We also evaluate preclinical evidence for cannabinoid-based combinations with conventional chemotherapy, targeted therapies, immunotherapies, and radiotherapy. Although in vitro and animal studies indicate that cannabinoids may reverse resistant phenotypes and enhance the activity of existing treatments, the translational relevance of these findings is limited by the predominance of cell-line and xenograft models, the paucity of clinical evidence for antitumor efficacy, pharmacokinetic constraints, potential drug-drug interactions, and context-dependent effects that may be neutral or adverse in certain immunological settings. Thus, while the endocannabinoid system represents a potential therapeutic target for sensitizing resistant hematologic malignancies, clinical translation will require validation at pharmacologically achievable exposures, the use of immunocompetent and clinically relevant models, identification of predictive biomarkers, and rigorous evaluation in prospective clinical studies.