Abstract:

Esophageal squamous cell carcinoma (ESCC) is a highly prevalent and lethal malignancy in China and other East Asian countries. For patients with locally advanced disease, neoadjuvant chemotherapy or chemoradiotherapy followed by surgery has become the standard treatment paradigm. However, despite improvements in local tumor control and surgical outcomes, long-term survival remains unsatisfactory, largely due to the high incidence of distant metastasis and systemic disease progression. Therefore, optimizing perioperative systemic therapy represents a critical unmet clinical need in ESCC. In recent years, the introduction of immune checkpoint inhibitors (ICIs) has profoundly reshaped the perioperative treatment landscape of ESCC. This review comprehensively summarizes recent clinical advances in perioperative immunotherapy for ESCC, including neoadjuvant immunotherapy alone, neoadjuvant immunotherapy combined with chemotherapy, neoadjuvant immunotherapy combined with chemoradiotherapy, and postoperative adjuvant immunotherapy. Current data indicate that neoadjuvant chemoradiotherapy remains highly effective in improving local control, downstaging tumors, and increasing the rate of R0 resection. Nevertheless, its ability to translate these advantages into durable survival benefit is limited, and distant recurrence remains a major cause of treatment failure. In contrast, neoadjuvant immunotherapy combined with chemotherapy has demonstrated a marked improvement in pathological complete response (pCR) rates across multiple early-phase trials. More importantly, this strategy appears to provide supe-rior systemic disease control, thereby reducing the risk of distant metastasis and offering a promising avenue for improving long-term survival. Neoadjuvant immunotherapy combined with chemoradiotherapy has shown further enhancement of local response and tumor regression; however, this approach is asso-ciated with increased treatment-related toxicity, and robust evidence supporting a clear survival advantage is still lacking. As a result, the optimal integration of radiotherapy into immunotherapy-based perioperative regimens remains an area of active investigation. Given the heterogeneity of ESCC, perioperative treatment strategies should evolve toward individualized, risk-adapted approaches. For patients with a high local tumor burden (advanced T stage), the incorporation of radiotherapy may be beneficial to reinforce local control and improve resectability. Conversely, for patients with extensive lymph node involvement (advanced N stage) and a high risk of distant relapse, immunotherapy-based systemic treatment should be prioritized. In the postoperative setting, adjuvant immunotherapy has been shown to improve outcomes in patients who fail to achieve pCR after neoadjuvant chemoradiotherapy. Looking forward, the integration of dynamic biomarkers, such as circulating tumor DNA (ctDNA), along with the identification of novel immune targets and predictive biomarkers, is expected to further refine patient selection and optimize precision perioperative treatment strategies for ESCC.

Key words: Esophageal squamous cell carcinoma, Perioperative therapy, Neoadjuvant immunotherapy, Pathological complete response