PLA2G2A drives gallbladder cancer progression by enhancing stemness and tumor immune suppression

Gallbladder cancer (GBC) is highly malignant, but the molecular mechanisms of its initiation and progression remain unclear. Our previous single-cell analyses identified phospholipase A2 group IIA (PLA2G2A) as an early-stage GBC marker potentially involved in cancer stemness regulation. Gain- and loss-of-function assays were conducted in vivo and in vitro to evaluate stemness, tumorigenicity, and chemoresistance. Protein interactions and downstream signaling pathways were investigated using co-immunoprecipitation, western blotting, and functional inhibition assays. The immunomodulatory role of PLA2G2A was assessed by measuring soluble PD-L1 (sPD-L1) secretion in cell lines and evaluating its effects on immune cells. PLA2G2A enhances GBC cell stem–like properties, including increased CD44 and CD133 expression, tumor-initiating capacity, and resistance to gemcitabine, which is consistent with the positive correlation between PLA2G2A and CD44/CD133 expression in clinical GBC samples. Mechanistically, PLA2G2A activates its receptor PLA2R1 and promotes its interaction with filamin A (FLNA), thereby triggering ERK1/2 signaling and inducing stemness-associated gene expression. Additionally, PLA2G2A induces soluble PD-L1 secretion to sustain an immunosuppressive tumor microenvironment, and its high expression correlates with infiltration of exhausted CD8 + T cells, M2 macrophages and Treg cells in clinical samples. Our findings clarify the multifaceted role of PLA2G2A in GBC progression by regulating cancer stemness and remodeling the tumor microenvironment, identifying it as a critical driver of GBC and providing a rationale for further investigating its therapeutic potential.