Molecular subtyping-guided precision therapy for ESCC: biomarker-driven strategies and clinical translation pathways

Esophageal squamous cell carcinoma (ESCC) is a highly aggressive malignancy with significant geographical disparities, particularly high in East Asia. The prognosis for advanced patients remains poor, largely due to profound intertumoral and intratumoral molecular heterogeneity, which drives variable treatment responses. This review delineates progress in molecular classification, where multiomics studies have defined distinct subtypes-cell cycle activated (CCA), NRF2-oncogenic activated (NRFA), immune suppressive (IS), and immune modulatory (IM)-each with specific therapeutic implications. This framework guides targeted therapies and predicts immunotherapy outcomes. We further evaluate biomarker-driven strategies (PD-L1, TMB, and NOTCH1 mutations) and emerging therapies targeting driver genes and the metabolic microenvironment. Translating subtyping into clinical practice requires validating strategies through innovative trial designs, establishing dynamic monitoring using liquid biopsy and spatial multiomics, and integrating multidimensional biomarkers. Constructing a molecular subtype-based precision medicine framework is pivotal to overcoming therapeutic limitations and improving survival in ESCC.