Survival benefit and dynamics of CD8+ T cells and tumor-associated macrophages in neoadjuvant immunochemotherapy vs. chemotherapy for locally advanced esophageal squamous cell carcinoma: an IPTW-adjusted real-world study

Background Neoadjuvant immunochemotherapy (nICT) has emerged as a promising strategy for patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC), yet real-world evidence comparing its efficacy and safety with conventional neoadjuvant chemotherapy (nCT) remains scarce. Furthermore, the underlying immune microenvironment dynamics associated with these clinical benefits have not been fully elucidated. Method We conducted a retrospective cohort study of patients with resectable LA-ESCC who received either nICT or nCT followed by curative esophagectomy. We used inverse probability of treatment weighting (IPTW) to minimize selection bias. The primary endpoints were overall survival (OS) and disease-free survival (DFS). In addition, we analyzed recurrence patterns and performed multiplex immunohistochemistry (mIHC) to characterize the immune microenvironment associated with treatment response. Results A total of 224 patients received nICT and 80 received nCT. After IPTW adjustment, OS in the nICT group was significantly better than in the nCT group (3-year OS: 77.68% vs . 67.49%; HR = 0.61, 95% CI: 0.37–0.98, P = 0.04). Notably, adjusted DFS did not differ significantly (P = 0.96). This discrepancy was driven by distinct recurrence patterns: distant organ metastasis was significantly lower in the nICT group (10.71% vs . 26.25%, P < 0.01). In exploratory analyses, nICT responders exhibited increased CD8 + T-cell infiltration and reduced M2-like macrophages (CD68 + HLA-DR - ), suggesting a shift from an immunosuppressive to an immune-activated microenvironment. Conclusion nICT provided a significant survival advantage over nCT, primarily by inhibiting distant metastasis rather than preventing local recurrence. This benefit may be attributed to immune microenvironment dynamics, specifically characterized by T-cell activation and macrophage modulation.