Immune checkpoint inhibitors have demonstrated promising efficacy and tolerable safety for advanced malignancies. However, a proportion of patients who had received immunotherapy may experience hyperprogressive disease and a resultant poor prognosis. Here, we report a patient with advanced esophageal squamous carcinoma who developed hyperprogressive disease shortly after immunotherapy. This patient received nivolumab after multiple lines of treatment, including chemotherapy, radiotherapy, and antiangiogenic therapy. Through the comprehensive analysis of NGS results, we concluded that the PI3K/AKT signaling pathway might be associated with hyperprogressive disease after immunotherapy. Additionally, potential mechanisms underlying hyperprogressive disease after immunotherapy reported in other malignant tumors were also summarized.