ARID1A deficiency-driven reprogramming of polyamine metabolism promotes endometrial cancer malignancy and immune escape

Abstract Metabolic reprogramming is crucial in developing endometrial cancer (EC); however, the mechanisms through which tumor suppressors control metabolites that drive cell proliferation and tumor growth remain unclear. ARID1A, an SWI/SNF chromatin remodeling complex subunit, is frequently mutated in endometrium-related malignancies. Here, EC tumors with ARID1A deleted exhibit increased polyamine production, which enhances malignant proliferative capacity while inhibiting the efficacy of functional CD8 + T cells. Mechanistically, ARID1A depletion in tumor cells interrupts the competitive binding of ARID1A to YAP, causing excessive YAP activation and transcriptionally increasing the expression of polyamine metabolic enzymes, thereby enhancing polyamine synthesis. Increased spermidine production from polyamines can directly hypusinate eukaryotic translation initiation factor 5A (eIF5A) at lysine residues, resulting in efficient histone demethylase LSD1 protein translation. Moreover, polyamine accumulation suppresses the recruitment of CD8 + T cells and hampers antitumor immune responses in vivo. Notably, polyamine depletion induced by eflornithine (DFMO) significantly reduces EC cell proliferative capacity and enhances CD8 + T-cell efficacy. Together, these findings highlight the role of ARID1A in regulating polyamine metabolism and suggest that elevated polyamine levels in tumors enhance malignant cellular behaviors and contribute to immune evasion by inhibiting CD8 + T cell-mediated cytotoxic responses. Therefore, targeting polyamine biosynthesis could be an important therapeutic strategy for ARID1A-inactivated EC.