Single-cell transcriptomics reveals the landscape of esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy and the potential resistance role of LGALS1

Background Neoadjuvant chemoradiotherapy (neoCRT) remodels the tumor microenvironment in esophageal squamous cell carcinoma (ESCC). This study aimed to analyze the impact of neoCRT on the immune landscape of ESCC and identify potential resistance genes using single-cell RNA-seq (scRNA-seq). Methods We obtained scRNA-seq datasets of ESCC from the GEO database and evaluated changes in the number and function of key T cells and myeloid cells following neoCRT. Malignant epithelial cells were analyzed using inferCNV and subjected to differential analysis to identify potential drug-resistance genes. The gene LGALS1, implicated in drug resistance, was further investigated. The effects of short hairpin RNA knockdown of LGALS1 on cisplatin sensitivity were assessed both in vitro and in vivo. Additionally, potential resistance pathways were explored through a protein-protein interaction network and gene set enrichment analysis. Results NeoCRT treatment resulted in the activation of T cells and myeloid cells within the tumor microenvironment, enhancing the anti-tumor immune response and improving tumor cell eradication compared to the surgery group. However, neoCRT simultaneously increased LGALS1 expression in tumor cells, which contributed to the development of drug resistance. Mechanistically, LGALS1 overexpression was associated with increased platinum resistance, enhanced DNA repair, resistance to apoptosis and epithelial-mesenchymal transition. Conclusion scRNA-seq analysis revealed that neoCRT significantly alters the immune landscape of ESCC. While neoCRT activates T cells and myeloid cells to target tumor cells effectively, it also induces LGALS1 overexpression, which contributes to drug resistance and potential relapse.