CELL INTELLIGENCE · 肿瘤细胞治疗研究

The efficacy of immune checkpoint blockade (ICB) in lung adenocarcinoma (LUAD) is limited by primary or acquired resistance, especially in genetically defined subsets. We investigated the impact of KRAS/TP53 co-mutation on ICB response. Our analysis reveals that KRAS/TP53 co-mutation is associated with favorable ICB outcomes, a phenotype orchestrated by secreted phosphoprotein 1 (SPP1). Mechanistically, mutant p53 and KRAS exert opposing effects on SPP1. Mutant p53 synergizes with transcription factor FOXA1 to repress SPP1 transcription, whereas KRAS activates the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK)-signal transducer and activator of transcription 1 (STAT1) axis to up-regulate SPP1 . Consequently, reduced SPP1 level in KRAS/TP53 co-mutant LUAD impairs myeloid-derived suppressor cell (MDSC) recruitment and increases CD8+ T cell infiltration. Notably, SPP1 blockade synergizes with anti-programmed death-1 (PD-1) therapy to suppress tumor growth in KRAS -mutant xenograft models. Collectively, we delineate a mutant p53-FOXA1-SPP1 regulatory axis that modulates ICB susceptibility and unveil a synergistic combination therapy strategy.