Transcriptional phenocopies of deleterious KEAP1 mutations dictate survival outcomes in lung cancer treated with immunotherapy.

Mutational models denoting KEAP1-NRF2 pathway activation have emerged as determinants of survival outcomes in non-small cell lung cancer (NSCLC). Hypothesizing that genetically distinct tumors recapitulate the transcriptional footprint of KEAP1 mutations (KEAPness), we identified a KEAP1-NRF2-related gene set shared by tumors with and without pathway mutations. KEAPness-dominant tumors were associated with poor survival outcomes and immune exclusion in two independent cohorts of immunotherapy-treated NSCLC (SU2C and OAK/POPLAR). Moreover, patients with KEAPness tumors had survival outcomes comparable to their KEAP1-mutant counterparts. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and an immune-excluded microenvironment, as highlighted by orthogonal methods for T cell estimation. This phenotypic state widely occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors. Collectively, we discovered the pervasive nature of the KEAPness phenotypic driver across evolutionary divergent tumors. This model outperforms mutation-based classifiers in predicting survival outcomes.