This study aims to evaluate the clinical efficacy of neoadjuvant chemoradiotherapy (NCRT), neoadjuvant chemotherapy (NCT), and neoadjuvant CT plus immunotherapy (NICT) in locally advanced esophageal squamous cell carcinoma (ESCC).

175 treatment-naïve patients with ESCC (clinical stage II-IV) undergoing neoadjuvant therapy were included. Clinical data were systematically extracted from institutional electronic health records, including pre/post-treatment TNM staging, treatment-related adverse events, and oncologic outcomes. The categories were compared for quantitative variables using a one-way ANOVA and the chi-square test of variance. A t-test was used for comparison of continuous variables, and categorical variables were compared by a χ2 test or Fisher’s exact test. Kaplan-Meier survival analysis was performed to generate curves, with intergroup comparisons conducted by the log-rank test.

All enrolled 175 patients underwent esophagectomy at Meizhou People’s Hospital between March 2020 and March 2024. Significant downstaging was observed in both postoperative T stages (t=-11.451, P < 0.001) and N stages (t=-10.272, P < 0.001) compared to baseline. Intergroup analysis revealed distinct therapeutic profiles. The NICT group demonstrated reduced postoperative nerve injury incidence compared to other modalities (χ²=7.811, P = 0.020), while no significant differences were observed in lymphovascular invasion rates or circumferential resection margins. Lymph node dissection analysis showed superior nodal yield in the NICT group versus NCRT (F = 4.88, P = 0.009), with correspondingly fewer metastatic lymph nodes in the NICT cohort compared to NCT alone (F = 4.256, P = 0.016). Notably, NCRT was associated with significantly longer neoadjuvant-to-surgery intervals compared to both NCT and NICT groups (F = 12.39, P < 0.001). No significant differences in recurrence rates were observed across treatment modalities during follow-up (χ²=0.530, P = 0.768). With a 28.5-month median follow-up, survival significantly differed between groups (log-rank p = 0.048). NICT had superior overall survival (median not reached vs. 31.2 months in NCRT and 34.5 months in NCT), with 2-year rates of 76.2%, 68.9%, and 63.3%, respectively.

NCRT, NCT, and NICT demonstrated effective tumor downstaging and surgical outcomes in locally advanced ESCC patients. Differences in surgical outcomes and adverse events highlight the potential benefits and considerations of combining immunotherapy with conventional treatments in this cohort.