For the NSCLC set, the PAPPA2-Mut group had significantly higher TMB (p < 0.001) than the PAPPA2-WT group (Figure 4E). In addition, a significant longer PFS was observed in patients with TMB-H and PAPPA2-Mut compared to those with TMB-L and PAPPA2-WT (HR, 0.16 [95% CI, 0.06–0.39]; p < 0.001; Figure 4F–G). Among all patients in the NSCLC set, those with TMB-H or PAPPA2-Mut (53/165) achieved significantly longer PFS (HR, 0.36 [95% CI, 0.23–0.57]; p < 0.001; Figure 4H) than counterparts....Our results demonstrated that patients with PAPPA2 mutation were associated with better clinical outcomes in ICIs treatment via activated immunogenicity and enhanced anti-tumour immunity. Thus, PAPPA2 mutation could act as a potential predictive biomarker for ICIs therapy in NSCLC.