Cannabinoid-driven epigenetic remodeling of a chromatin-lipid homeostatic axis via ARID1A uncovers a metabolic vulnerability in cancer

A substantial body of evidence supports a tumor suppressor role for the chromatin remodeler ARID1A, whose inactivating mutations and loss of function are common across human cancers. These alterations have spurred extensive efforts to uncover vulnerabilities associated with ARID1A deficiency. However, emerging studies suggest that ARID1A may also exert context-dependent tumor-promoting functions, opening new therapeutic avenues in ARID1A-proficient tumors. In endometrial cancer (EC), ARID1A mutations typically arise late during tumor progression and are dispensable for tumor initiation, providing a relevant context to interrogate its noncanonical homeostatic roles. Here, through integrated multiomics analyses, cellular bioenergetics and in vivo studies using EC patient-derived xenografts and genetically engineered mouse models, we demonstrate that functional ARID1A is required for acquired resistance to nutrient deprivation induced by antiangiogenic (starvation) therapy. Mechanistically, ARID1A orchestrates an epigenetically regulated chromatin-lipid homeostatic program involving lipid metabolism and mitochondrial fatty acid oxidation. Unexpectedly, we find that Δ9- tetrahydrocannabinol (THC), a phytocannabinoid and orthosteric CB1/CB2 agonist, exerts its antitumor activity by repressing ARID1A, thereby dismantling this chromatin- lipid metabolic axis and restoring sensitivity to starvation therapy. These findings position ARID1A as a central node linking chromatin remodeling to metabolic plasticity, and identify THC as a pharmacologic disruptor of this epigenetic metabolic program with therapeutic potential in ARID1A-proficient tumors.