Neoadjuvant immunotherapy for resectable esophageal cancer: Research progress and clinical perspectives

Esophageal cancer is one of the most aggressive malignant tumors. It primarily comprises two pathological subtypes, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), each requiring distinct therapeutic strategies. Overall, neoadjuvant chemotherapy (nCT) and neoadjuvant chemoradiotherapy (nCRT) have been established as standard treatment modalities recommended by international guidelines. However, challenges such as high recurrence rates, inadequate control of distant metastases, and perioperative toxicities persist. With the success of immune checkpoint inhibitors (ICIs) in advanced esophageal cancer, investigators have begun to explore their use in the neoadjuvant or perioperative setting, aiming to improve long-term outcomes by enhancing pathological response rates, eradicating micrometastases, and inducing durable antitumor immunity. This narrative review comprehensively synthesizes the latest clinical evidence regarding neoadjuvant immunotherapy in resectable esophageal cancer, including monotherapy with ICIs, combinations of ICIs with chemotherapy, and combinations of ICIs with chemoradiotherapy. It further compares therapeutic efficacy between ESCC and EAC and elucidates the biological mechanisms underlying these disparities. Based on these findings, practical clinical pragmatic considerations are discussed, covering drug selection, cycle design, surgical timing, and perioperative safety management. Current clinical trial data suggest that while neoadjuvant immunochemotherapy shows improved pathological response rates with acceptable safety particularly in resectable ESCC, definitive evidence regarding long-term survival benefits remains unproven. Furthermore, its efficacy in EAC remains limited. Key clinical questions such as optimizing drug combinations, defining the ideal treatment duration and surgical timing, and balancing the benefits and risks of combining immunotherapy with radiotherapy remain unresolved and warrant further investigation through large-scale randomized controlled trials. Future research should prioritize the development of predictive biomarkers derived from multi-omics analyses and the use of adaptive clinical trial designs to carefully evaluate organ-preserving strategies, potentially shifting treatment toward a more individualized approach.