Clinical utility of circulating tumor cell PD-L1 expression for predicting immunotherapeutic response and prognosis in esophageal cancer

Background Immune checkpoint inhibitors (ICIs) have improved outcomes in esophageal cancer, yet reliable biomarkers remain lacking. Tissue PD-L1 testing is limited by intratumoral heterogeneity and invasiveness, whereas circulating tumor cells (CTCs) offer a non-invasive alternative. This study evaluated CTC PD-L1 expression as a predictive and prognostic biomarker in patients with advanced esophageal cancer receiving chemo-immunotherapy. Methods A total of 93 patients with stage III–IV esophageal cancer were enrolled. The primary biomarker analysis was restricted to 59 patients who received chemo-immunotherapy, while 34 patients treated with chemotherapy alone were analyzed separately. Baseline CTCs were isolated and PD-L1 expression assessed, alongside tissue PD-L1 (tPD-L1) by immunohistochemistry. Associations with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated using ROC curves and univariate and multivariable Cox regression. Results CTC positivity correlated significantly with advanced stage, metastasis ( p = 0.0411), and larger tumor size ( p = 0.0454). In the chemo-immunotherapy cohort, CTC PD-L1 positivity was associated with a higher ORR (75.0% vs. 29.6%, p < 0.001) and showed moderate predictive ability (AUC = 0.7049, p = 0.0037). CTC PD-L1 positivity was significantly associated with OS (HR = 0.254, p = 0.002), but not significantly with PFS in univariate analysis (HR = 0.546, p = 0.042; Kaplan–Meier p = 0.061). Conversely, tPD-L1 status was not significantly associated with PFS or OS (both p > 0.05). In multivariable analysis adjusting for age, sex, histological subtype, stage, metastasis, and treatment modality, CTC PD-L1 remained an independent prognostic factor for PFS (HR = 0.488, p = 0.039) and OS (HR = 0.244, p = 0.002). Conclusions Baseline CTC PD-L1 expression was associated with favorable response and OS in patients receiving chemo-immunotherapy, and may complement tissue testing. These exploratory findings require prospective validation in larger cohorts before clinical use.