cPLA2α inhibition potentiates anti-PD-1 immunotherapy in lung adenocarcinoma via remodeling tumor microenvironment.

Although immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 have revolutionized lung adenocarcinoma (LUAD) therapy, resistance and low response rates persist. Cytoplasmic phospholipase A2α (cPLA2α), a key enzyme in inflammatory pathways, promotes tumor progression, yet its immunomodulatory role in LUAD is unclear. Here, cPLA2α overexpression is found in LUAD tissues, correlating with poor prognosis. cPLA2α knockdown inhibits lung cancer cell proliferation, migration in vitro, and tumor growth in immunodeficient mice, but efficacy diminishes in immunocompetent models due to STAT3-mediated PD-L1 upregulation. In syngeneic models, cPLA2α silencing promotes CD8+ T cell and M1 macrophage infiltration and reduces immunosuppressive neutrophils and M2 macrophages. Strikingly, cPLA2α knockdown with anti-PD-1 synergistically suppresses tumor growth, where granzyme B+ cytotoxic CD8+ T cells amplifies. Our findings unveils cPLA2α's dual role in LUAD: promoting tumorigenesis and orchestrating immune evasion via STAT3-PD-L1 signaling. Targeting cPLA2α may overcome PD-1 blockade resistance, particularly benefiting patients with high cPLA2α and low baseline PD-L1. This study highlights cPLA2α as a promising therapeutic target to enhance ICI efficacy and reshape LUAD immunotherapy strategies.