Background: Immune checkpoint inhibitors (ICIs) have emerged as a pivotal treatment for advanced esophageal squamous cell carcinoma (ESCC). However, their efficacy can significantly differ among #Patients, highlighting the need for reliable prognostic markers to enhance treatment outcomes. Lactate dehydrogenase (LDH) plays a key regulatory role in the complex relationship between #Cancer metabolism and the immune system, suggesting that monitoring LDH levels may provide valuable insights into treatment efficacy and inform personalized therapeutic strategies for advanced ESCC. Objective: This #Study explores the prognostic significance of dynamic changes in LDH levels during ICI therapy in predicting treatment outcomes. Methods: We retrospectively analyzed clinical data from 126 #Patients with advanced ESCC treated with first-line ICIs. Serum LDH levels were measured after every two cycles of combined immunotherapy and chemotherapy. Receiver operating characteristic curve analysis determined the optimal LDH reduction threshold. Kaplan-Meier survival curves and Cox regression models assessed progression-free survival (PFS) and overall survival (OS). Results: LDH decrease following first-line ICI therapy was associated with improved outcomes compared to LDH increases (median PFS: 9.5 vs. 5.4 months, p = 0.004). #Patients with an LDH decrease of more than 14.4% post-treatment had a median PFS of 11.1 months. Those with an LDH decrease between 0% and 14.4% had a median PFS of 21.7 months. Conversely, an increase in LDH levels resulted in a median PFS of 10.8 months. Significant PFS improvement was observed in #Patients with LDH reductions after two cycles of immunotherapy (p < 0.01). Multivariate analysis identified LDH decrease as an independent predictor of a 41% lower mortality risk (OR: 0.59, 95% CI: 0.36–0.96, p = 0.035). Conclusions: In #Patients with advanced ESCC, a decrease in serum LDH levels ranging from 0% to 14.4% after treatment initiation was significantly associated with prolonged PFS. Notably, an early decrease in LDH levels observed after two cycles of immunotherapy further correlated with improved clinical outcomes. These results highlight the potential of LDH as a valuable biomarker for risk stratification and personalized treatment optimization in advanced ESCC.

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