Optimal Neoadjuvant Approach for Resectable Esophageal Cancer in the Era of Immunotherapy

Neoadjuvant immunotherapy has emerged as a promising strategy for patients with resectable esophageal cancer (EC), yet the optimal therapeutic approach remains unclear. We performed an updated network meta-analysis to compare the efficacy and safety of current neoadjuvant immunotherapy-based strategies using the most recent prospective randomized controlled trials. Eligible studies published before August 1, 2025 were systematically identified, and a Bayesian network meta-analysis with Markov chain Monte Carlo methods was conducted. The primary endpoints were pathological complete response (pCR) and major pathological response (mPR), while secondary outcomes included objective response rate (ORR), R0 resection rate, grade ≥ 3 treatment-related adverse events (tr-AEs), and survival outcomes. A total of 41 trials involving 4624 patients were included. Neoadjuvant immunotherapy combined with chemoradiotherapy followed by surgery (nICRT+S) achieved the highest pCR rate and demonstrated superior efficacy compared with other neoadjuvant approaches. Neoadjuvant immunotherapy combined with chemotherapy (nICT+S) showed the greatest probability of ranking first in improving mPR and ORR. Importantly, the addition of immunotherapy or radiotherapy did not increase the incidence of grade ≥ 3 tr-AEs, and maintenance immunotherapy after surgery did not confer additional survival benefit based on the currently available evidence with limited follow-up. Overall, these findings indicate that nI(C)RT+S may represent the most effective neoadjuvant strategy for patients with resectable EC, offering improved tumor response without increasing treatment-related toxicity.