Locoregionally advanced laryngeal and hypopharyngeal cancers (LA-LHCs) are traditionally treated with surgery followed by postoperative radiotherapy, which impairs speech and swallowing functions and reduces the quality of life.1,2 The use of induction chemotherapy (IC) as a larynx-preserving approach for LA-LHCs has been verified and refined.3 However, the short-term tumor response to IC varies, non-responders usually show poor survival and little benefit.4 Therefore, it is crucial to identify IC responders and avoid ineffective treatment. We sought to develop and independently validate a gene-expression signature to predict the efficacy of IC in LA-LHC patients, which would help clinicians select patients who would benefit from IC and provide individual advice for precision treatment, paving the way toward biomarker-driven treatment strategies (Fig. 1).