Cannabinoids in Combination with Conventional Breast Cancer Therapies: Mechanistic Insights and the Gap to Clinical...

Current treatments for breast cancer (BC) include surgery, radiation, chemotherapy, targeted therapy, hormonal therapy, and immunotherapy. However, adverse effects such as pain, nausea, cardiotoxicity, and neuropathy have prompted interest in complementary approaches. Cannabinoids (CBS), particularly cannabidiol and delta-9-tetrahydrocannabinol, are already used by cancer patients for symptom relief, and preclinical studies in cell culture and mouse models suggest additional therapeutic potential at the cellular level: combining CBS with chemotherapy may sensitize tumour cells to chemotherapeutic agents, inhibit tumour proliferation, and increase apoptosis. In murine models, such combinations may also mitigate chemotherapy-induced cardiotoxicity by enhancing antioxidant activity, modulating cannabinoid receptor signalling to reduce pro-inflammatory markers, and restoring mitochondrial function in myocytes. In addition, CBS may augment hormonal therapy in estrogen receptor-positive (ER+) BC cells, primarily via aromatase inhibition and modulation of ER and EGR3 signalling. Notably, evidence on combining CBS with targeted therapies in BC is lacking, while studies of CBS-immunotherapy combinations have been conducted in non-BC cancers; in BC, they are scarce and limited to in vitro models. This represents a key area for future research, particularly given the heterogeneity across non-BC cancers, where CBS-immunotherapy combinations have demonstrated mixed effects, both beneficial and detrimental (e.g., reduced response rates and overall survival), with the underlying mechanisms remaining unclear. Translation of these findings into clinical practice faces several challenges. Although over 120 CBS have been identified, only a few are well-characterized. CBS exhibit diverse mechanisms and effects, including potential adverse outcomes and interactions with conventional therapies (e.g., effects on chemotherapeutic drug metabolism). Variability among BC cells may also result in differing responses to the same therapeutic combinations. Future research should delineate the effects of individual CBS in combination strategies and prioritize well-controlled, standardized clinical studies to build on in vitro and animal data, while also exploring genetically informed personalized approaches. Ultimately, clinical guidelines specifying CBS type, formulation, and delivery are needed.