Current research status and challenges of neoadjuvant immunotherapy for Esophageal squamous cell carcinoma.

Neoadjuvant immunotherapy (NIT) is transforming the treatment landscape for esophageal squamous cell carcinoma (ESCC), substantially improving the pathological complete response (pCR) rates achieved with traditional chemoradiotherapy. Clinical trials demonstrate that combining PD-1 inhibitors such as pembrolizumab or camrelizumab with chemotherapy markedly increases pCR rates to over 40% and 28%, respectively. The efficacy of NIT is attributed to immune checkpoint inhibitors (ICIs) remodeling the tumor microenvironment, including expanding pre-exhausted SPRY1+CD8+ T cells and promoting M1 macrophage polarization. While conventional biomarkers like PD-L1 have limited predictive value, novel tools such as SPRY1+CD8+ T cell infiltration, the EN-ImiRPS model, and dynamic ctDNA monitoring offer superior predictive accuracy for treatment response. These advances enable more personalized strategies: patients with high PD-L1 expression may benefit from ICI monotherapy, and those achieving a clinical complete response (cCR) with ctDNA negativity can explore non-surgical organ preservation, with encouraging survival outcomes. For patients without pCR after surgery, adjuvant nivolumab extends disease-free survival. However, primary resistance remains a challenge, driven by mechanisms such as M2 macrophage suppression and cancer stem cell escape. Future efforts should focus on multi-omics biomarker integration, optimizing de-escalation strategies for responders, and targeting resistant pathways within the tumor microenvironment to establish a new paradigm of chronic disease management for ESCC.