Neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin for locally advanced, resectable esophageal squamous cell carcinoma: clinical study and mechanistic exploration

The survival benefits of neoadjuvant chemotherapy combined with immunotherapy in locally advanced esophageal squamous cell carcinoma (ESCC) remain unclear, with treatment responses varying due to tumor microenvironment (TME) heterogeneity. In this phase II study, 24 patients received neoadjuvant sintilimab, albumin-bound paclitaxel, and carboplatin, with major pathological response (MPR), disease-free survival (DFS), and overall survival (OS) as primary endpoints. Results showed a 41.7% MPR rate, with 3 year DFS and OS rates of 75.0% and 79.2%, respectively. The PD-L1 expression of all patients increased during treatment; and its post-treatment levels were more strongly associated with the response to PD-1 inhibitors than pre-treatment levels. Besides, the mass spectrometry-based proteomic quantification identified 9 downregulated proteins in responders, including immune regulation-related proteins and peptidyl-serine phosphorylation proteins, revealing the TME changes linked to therapy efficacy. Additionally, 14 differentially expressed proteins were found at baseline between responders and non-responders, with high CD44 expression correlating with a favorable anti-PD-1 response. Post-treatment analysis revealed 27 differential proteins, 10 of which negatively correlated with efficacy. In conclusion, neoadjuvant sintilimab plus chemotherapy demonstrates promising efficacy and safety. Proteomic profiling of the TME further elucidates the heterogeneity of immunotherapy responses, offering insights for precision strategies in ESCC neoadjuvant therapy. Trial registration This study was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR2000041081).