Transient CB2R Modulation Promotes Luminal-like Differentiation and Restricts Breast Cancer Plasticity

Cancer cell plasticity enables therapy resistance and metastasis by allowing transitions between stem-like and differentiated states. Differentiation-based strategies aim to stabilize tumor cell identity, yet pharmacological approaches that induce durable lineage restriction remain limited. Here, we show that transient modulation of cannabinoid receptor 2 (CB2R) promotes persistent luminal-like stabilization in breast cancer models. Using patient-derived and murine tumor organoids, we demonstrate that brief, low-dose CB2R modulation reduces self-renewal, invasiveness and tumor-initiating capacity, while enhancing tamoxifen sensitivity and limiting the emergence of resistant phenotypes. These effects persist under pro-dedifferentiation conditions, including TGFb exposure, stromal co-culture, immune signaling and mechanical stress, and are long-term maintained in vivo following orthotopic transplantation. RNAseq analyses reveal a trajectory from an early plastic state toward a stabilized luminal-like identity, supported by CUT&Tag profiling that uncovers chromatin remodeling in this transition. Together, our findings redefine CB2R as a regulator of tumor cell state rather than solely a mediator of cytotoxic responses and establish transient CB2R modulation as a strategy to durably constrain breast cancer plasticity through differentiation-based therapy.