<p>Lymph node metastasis (LNM) indicates aggressive tumor biology, which is associated with poor prognosis in esophageal squamous cell carcinoma (ESCC). However, comprehensive and in-depth research on the immunophenotyping of ESCC patients with LM remains limited, and effective indicators for the preoperative LNM diagnosis and prognosis assessment in ESCC are urgently needed in clinical practice. Therefore, we performed deep immunophenotyping of peripheral blood samples from ESCC patients and age- and sex-matched healthy controls, revealing a distinct landscape of immune dysfunction in peripheral blood of ESCC patients with LNM. Specifically, innate immunity exhibited impaired antigen presentation capacity, evidenced by decreased CD86 and HLADR expression on monocytes and mDCs. Compromised innate immune response was demonstrated by significantly attenuated IL-6 production following toll-like receptor 2 agonist stimulation in ESCC patients with LNM. Furthermore, adaptive immunity displayed increased CD38⁺ T cells concurrent with decreased CD28⁺ T cells and CD8⁺ T_CM cells, indicating T cell hyporesponsiveness. Decreased Tconv/Treg and Tfh/Tfr ratios revealed an immunosuppressive state. Notably, an integrated three-parameter random forest model presented considerable discriminatory power for preoperative LNM diagnosis (AUC = 0.96), with Tfh cells providing the highest contribution to diagnostic accuracy. Moreover, a nomogram incorporating memory Treg cells demonstrated excellent predictive capacity for 3-year mortality (AUC = 0.94). These findings demonstrate that peripheral blood immune phenotypes could serve as effective indicators for both preoperative LNM diagnosis and postoperative prognosis in ESCC, potentially improving clinical decision-making.</p>