Esophageal cancer is an aggressive malignancy often diagnosed at advanced stages, with esophageal squamous cell carcinoma being the predominant subtype worldwide. Standard first-line chemotherapy provides limited survival benefits, with a median overall survival of less than 1 year. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors (ICIs), have transformed the treatment landscape, improving overall survival and progression-free survival. However, response rates remain variable, with programmed death ligand 1 (PD-L1) expression being the primary predictive biomarker. The variability in PD-L1 testing methods and immune microenvironment alterations after prior treatments complicate patient selection for ICIs. Several phase 3 trials, including KEYNOTE-590 and CheckMate 648, have demonstrated the efficacy of ICIs combined with chemotherapy, particularly in patients positive for PD-L1. Despite these advances, long-term survival remains low, emphasizing the need for better biomarkers and novel therapeutic strategies. This review explored current first-line treatment options for esophageal squamous cell carcinoma, challenges in biomarker-based patient selection, and emerging therapeutic approaches.