OBJECTIVE: To explore the clinical value of molecular residual disease detection based on circulating tumor DNA (ctDNA-MRD) in the perioperative period of esophageal squamous cell carcinoma (ESCC) and to analyze the tumor escape mechanisms in MRD-positive cases. METHODS: A total of 35 ESCC patients were prospectively enrolled. Preoperative and postoperative (1 month after surgery) blood and surgical tissue samples were analyzed. ctDNA variants were tracked in plasma to assess ctDNA-MRD, and whole-transcriptome sequencing was performed on MRD-positive and MRD-negative tissue samples. RESULTS: Preoperative blood ctDNA was positive in 54.3% of patients, with a 31.6% positive predictive value for recurrence. One month postsurgery, the positive rate of ctDNA was 17.1%, with an 83.3% predictive value for recurrence. Both preoperative and postoperative ctDNA positivity were significant prognostic indicators (HR = 2.78, p <
0.05
HR = 4.42, p <
0.001). Multivariate analysis confirmed ctDNA as an independent prognostic factor (HR = 303.75, p <
0.001). Transcriptomic analysis revealed increased macrophage (W = 15 848
p <
0.01) and follicular helper T (Tfh) cell (W = 10 935
p <
0.01) levels in MRD-positive patients, suggesting a potential link to immune escape in tumors. CONCLUSIONS: Plasma ctDNA measured 1 month postoperatively in ESCC patients can effectively detect MRD, and ctDNA-MRD serves as an independent risk factor for postoperative recurrence. The mechanism underlying MRD positivity may involve the polarization of Tfh cells and macrophages, aiding tumor cells in immune escape through the bloodstream.