Circulating genomic biomarkers predict chemoradiotherapy resistance and immunotherapy response in locally advanced non‐small‐cell lung cancer

Abstract Predicting the effect of consolidation immunotherapy after chemoradiotherapy (CRT) for unresectable locally advanced non‐small‐cell lung cancer (LA‐NSCLC) patients remains a challenge, given the restricted sensitivity of single circulating tumor DNA (ctDNA) molecular residual disease (MRD) detection. In this study, 384 longitudinal blood samples from 160 patients with LA‐NSCLC undergoing CRT ± consolidation immunotherapy, tumor tissue whole‐genome or whole‐exome sequencing (WGS/WES) from 421 LA‐NSCLC patients treated with radiotherapy, and RNA‐sequencing data from 1149 subjects are analyzed. Pretreatment ctDNA‐based STK11(LKB1)/KEAP1 mutations are associated with poor prognosis and resistance to CRT but suggest benefits from consolidation immunotherapy after CRT. WGS/WES data confirm that STK11/KEAP1 ‐mutated tumors are radiotherapy‐resistant. RNA‐sequencing reveals an immunosuppressive tumor microenvironment for STK11/KEAP1 ‐mutated patients, characterized by strikingly decreased Th17 cells through the IL‐17 signaling downregulation, which could cause impaired response to upfront CRT but improved immunotherapy response after radiotherapy‐activated immunity. Predictive performance with individual ctDNA‐MRD detection is limited, while combining baseline STK11/KEAP1 mutations with ctDNA‐MRD effectively enhances prediction sensitivity, particularly in MRD‐negative patients. Integrating genomics with liquid biopsies could inform personalized and risk‐adaptive therapeutic decisions on consolidation immunotherapy.