The study investigates the predictive value of KRAS and TP53 co-mutations in lung adenocarcinoma patients treated with immune checkpoint inhibitors (ICIs). The research involved 713 patients with advanced lung adenocarcinoma from the Thoraxklinik Heidelberg, who were treated with ICIs. The study also included two external cohorts for validation. Univariate and multivariate survival analyses showed that KRASmut/TP53mut tumors had significantly better overall survival (OS) and progression-free survival (PFS) compared to other mutation configurations, both in the Heidelberg cohort and in external validation cohorts. The increased benefit from ICI was confirmed in two external cohorts of patients treated with ICI and two cohorts of surgically treated patients who did not receive ICI. Molecular analysis revealed that KRASmut/TP53mut tumors exhibited higher tumor mutational burden (TMB), proliferation, and PD-L1 mRNA expression, but these features were not specific to this mutation combination. Genome-wide expression analysis identified 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristics of KRASmut/TP53mut tumors. The study concludes that KRAS/TP53 co-mutation is a strong predictor of ICI benefit and is associated with unique molecular tumor features, which can be easily assessed using small NGS panels.The study investigates the predictive value of KRAS and TP53 co-mutations in lung adenocarcinoma patients treated with immune checkpoint inhibitors (ICIs). The research involved 713 patients with advanced lung adenocarcinoma from the Thoraxklinik Heidelberg, who were treated with ICIs. The study also included two external cohorts for validation. Univariate and multivariate survival analyses showed that KRASmut/TP53mut tumors had significantly better overall survival (OS) and progression-free survival (PFS) compared to other mutation configurations, both in the Heidelberg cohort and in external validation cohorts. The increased benefit from ICI was confirmed in two external cohorts of patients treated with ICI and two cohorts of surgically treated patients who did not receive ICI. Molecular analysis revealed that KRASmut/TP53mut tumors exhibited higher tumor mutational burden (TMB), proliferation, and PD-L1 mRNA expression, but these features were not specific to this mutation combination. Genome-wide expression analysis identified 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristics of KRASmut/TP53mut tumors. The study concludes that KRAS/TP53 co-mutation is a strong predictor of ICI benefit and is associated with unique molecular tumor features, which can be easily assessed using small NGS panels.