In this study, we performed an integrated genomic, transcriptomic, and proteomic analysis on 240 treatment-naïve NPC cases received GP induction chemotherapy plus CCRT or CCRT alone. Genetic alterations and signatures of intratumor IgA are identified to predict survival benefit from GP induction chemotherapy, which is validated in a phase III multi-center clinical cohort. Additionally, the comprehensive multi-omic profiling reveals three molecular subtypes with distinct immunologic features and GP induction chemotherapy benefits, which implicates potential therapeutic vulnerabilities to guide precision treatment strategy.