Neoadjuvant and Perioperative Immunotherapy for Resectable Esophageal Squamous Cell Carcinoma: Current Evidence, Endpoints, and Clinical Integration.

Immune checkpoint inhibitors (ICIs) are being investigated across curative-intent treatment pathways for resectable esophageal squamous cell carcinoma (ESCC). Randomized studies show that programmed cell death-1 blockade can increase pathological complete response (pCR) when added to neoadjuvant chemotherapy, while immunochemoradiotherapy can produce high pathological response rates. This structured narrative review summarizes current evidence for neoadjuvant and perioperative immunotherapy in ESCC within the context of established chemotherapy and chemoradiotherapy backbones. Particular attention is given to randomized ICI trials, the role of radiotherapy, interpretation of pathological and survival endpoints, circulating tumor DNA (ctDNA), postoperative therapy, perioperative safety, clinical response assessment, and regional applicability. pCR is a useful early activity endpoint and may carry prognostic information within individual regimens, but definitions and pathological assessment vary and trial-level surrogacy for overall survival has not been established. Longitudinal ctDNA is promising as a complementary measure of molecular residual disease but remains investigational for treatment adaptation. When radiotherapy is combined with ICI, established thoracic organ-at-risk constraints and careful monitoring for overlapping pulmonary and esophageal toxicity remain important because ICI-specific normal-tissue constraints have not been validated. Clinical complete response assessment also requires multimodal evaluation; post-treatment inflammatory changes can limit CT and PET-CT specificity. Overall, current data support continued phase III evaluation of ICI-containing strategies with mature event-free and overall survival endpoints and with comparators appropriate to regional treatment standards.