Esophageal cancer is an aggressive and common malignancy in Asian countries. Due to late diagnosis and limited treatments, the prognosis of esophageal cancer is still very poor. Although immune checkpoint inhibitors have become promising second-line treatments for esophageal cancer, there are limited evidences for first-line treatments. Here, we reported a case of successful treatment beyond progression with chemo-immunotherapy for esophageal squamous cell carcinoma (ESCC). Combined with local resection of several metastases during chemo-immunotherapy, the patient achieved a long survival time of 22 months and a good quality of life. Samples of the primary tumor and three metastases of testicle, skin nodule and left adrenal were obtained to perform whole exome sequencing (WES), RNA sequencing and immunohistochemistry. The skin nodule metastasis was resected after partial response, while the other two metastases of testicle and adrenal gland were removed after disease progression. Immunohistochemistry results exhibited low/negative PD-L1 expression and WES results showed intermediate TMB and MSI-L for all three lesions. However, RNA sequencing results presented a higher percentage of infiltrating CD8(+) T cells, higher signature scores of T cell status and higher expression level of human leukocyte antigen (HLA) genes in skin nodule metastasis than the other two metastases. This case provided a clinical evidence of beneficial treatment beyond progression with chemo-immunotherapy for ESCC. In addition, tumor microenvironment might be essential for clinical responses at the sampling time point.