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Neoadjuvant therapy has become the standard of care for locally advanced esophageal cancer; however, a subset of patients still faces the dilemma of treatment failure, characterized by clinical progression or failure to achieve R0 resection. The predominant recurrence patterns are distant metastasis and locoregional recurrence. This failure is a multidimensional consequence of patient characteristics, treatment modalities, and hospital volume. To address this clinical challenge, this article systematically explores individualized breakthrough strategies. The first is the perioperative "intensification and salvage" strategy, encompassing the re-evaluation of salvage surgery at high-volume centers, the intensification and conversion of systemic therapies (e.g., novel agents like bispecific ADCs), the individualized application of precision radiotherapy, and the standardized intervention of postoperative adjuvant immunotherapy (e.g., PD-1 inhibitors). The second strategy is molecular residual disease (MRD)-guided precision adjuvant therapy, utilizing liquid biopsy technologies such as ctDNA to implement an adaptive management model-intensifying treatment for MRD-positive patients while de-escalating or observing for MRD-negative ones. In the future, the clinical management of esophageal cancer will shift from passive "post-failure salvage" to proactive "whole-process prediction and adaptive management," aiming to further optimize treatment pathways and improve patient prognosis.