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LGALS1 drives chemoresistance in esophageal squamous cell carcinoma by modulating epithelial-mesenchymal transition and tumor immunity
Qi-Hang Yan, Chen-Di Xu, Zhen-Guo Li, Yu-Zhen Zheng, Wing-Shing Wong, Da-Chuan Liang, Jie Yang, Wu-Guang Chang, Jun-Ye Wang
Qi-Hang Yan, Chen-Di Xu, Zhen-Guo Li, Wing-Shing Wong, Da-Chuan Liang, Jie Yang, Jun-Ye Wang, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
Qi-Hang Yan, Zhen-Guo Li, Yu-Zhen Zheng, Wing-Shing Wong, Jun-Ye Wang, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
Yu-Zhen Zheng, Biomedical Innovation Center, Department of Thoracic Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, Guangdong Province, China
Wu-Guang Chang, Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China
Co-first authors: Qi-Hang Yan and Chen-Di Xu.
Co-corresponding authors: Wu-Guang Chang and Jun-Ye Wang.
Author contributions: Yan QH and Xu CD have played important and indispensable roles in the experimental design, data interpretation and manuscript preparation as co-first authors; Yan QH, Xu CD, and Li ZG conducted the study and wrote the manuscript; Zheng YZ, Wong WS, Liang DC, Yang J and Chang WG performed the bioinformatics analysis and data analysis; Chang WG and Wang JY design the research plan as co-corresponding authors; all authors reviewed and approved the manuscript.
Supported by National Natural Science Foundation of China, No. 82173293.
Institutional review board statement: This study was conducted ethically in accordance with the World Medical Association Declaration of Helsinki and approved by the Sun Yat-sen University Cancer Center Ethics Committee (No. SL-B2024-312-01).
Institutional animal care and use committee statement: The protocols for animal experiments were approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University (No. L102012024070D), the tumor diameter of the mice in this study did not exceed 20 mm, which was in line with the laboratory animal management regulations of the National Institutes of Health of the United States.
Conflict-of-interest statement: All authors declare no conflict of interest in publishing the manuscript.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Corresponding author: Jun-Ye Wang, MD, Professor, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, No. 651 Dongfeng East Road, Guangzhou 510060, Guangdong Province, China.
wangjy@sysucc.org.cn
Received: November 18, 2025
Revised: December 18, 2025
Accepted: January 27, 2026
Published online: May 14, 2026
Processing time: 168 Days and 23.6 Hours
BACKGROUND
Esophageal cancer represents one of the most prevalent malignant tumors globally. Esophageal cancer lack of tumor markers in clinical diagnosis, unable to effectively monitor development, drug resistance and prognosis of tumor, lead to clinical treatment effect is poorer. Neoadjuvant chemoradiotherapy (neoCRT) can substantially enhance the prognosis for individuals diagnosed with locally advanced esophageal squamous cell carcinoma (ESCC). Nevertheless, treatment resistance still occurs, affecting the long-term survival of patients.
AIM
To investigate the genes and regulatory mechanisms associated with platinum-based resistance in ESCC.
METHODS
In this investigation, single-cell RNA sequencing results of ESCC were analyzed to obtain the dynamic remodeling of tumor microenvironment in ESCC patients following neoCRT. Six ESCC samples were analyzed for scRNA-seq analysis. Four patients achieved partial response after neoCRT and then underwent surgery, and 2 patients received surgery alone. Multiple immunofluorescence and western blot were used to verify the expression of characteristic genes and the distribution of tumor cells. Gene knockdown, cholecystokinin-8, flow cytometry, colony formation, and subcutaneous tumorigenesis were used to validate the role of signature genes in the development of platinum-resistant ESCC.
RESULTS
Analysis showed that individuals with ESCC after neoadjuvant chemoradiation, expressed in the tumor cell toxicity molecular effect of CD8+ T cell infiltration, inflammation macrophages subgroup abundance increase, LAMP3+ dendritic cell activation, increase antitumor immune response. However, some residual malignant epithelial cells still survived, indicating that these cells may have drug resistance and the possibility of relapse. We analyzed this part of the cell gene expression, and screening to LGALS1 gene may be associated with drug resistance. LGALS1 exhibits elevated expression levels in tumor cells and is linked to cisplatin resistance. Functional verification indicated that knockdown of LGALS1 expression could up-regulate the sensitivity of esophageal squamous cell cells and tumors to cisplatin therapy by inhibiting intracellular epithelial-mesenchymal transformation, DNA damage repair and anti-apoptosis mechanisms.
CONCLUSION
These findings confirm LGALS1 is the key of ESCC of platinum resistance protein, targeted LGALS1 may be an effective means to overcome the neoadjuvant chemoradiation resistance.
Core Tip: In this investigation, we comprehensively characterized the dynamic changes in the immune microenvironment during treatment by analyzing single-cell RNA sequencing data of esophageal squamous cell carcinoma (ESCC) patients who underwent neoadjuvant chemoradiotherapy. LGALS1 was found to be a gene associated with neoadjuvant chemoradiotherapy resistance in ESCC. Subsequent experimental validation demonstrated LGALS1’s contribution to cisplatin resistance in ESCC through both in vitro and in vivo investigations. These studies illustrate ESCC cisplatin drug treatment failure mechanisms, emphasized the LGALS1 can serve as a promising therapeutic target. It also reveals a potential strategy to overcome the development of cisplatin resistance in ESCC, laying a foundation for the development of more effective individualized treatment regimens, and potentially leading to better outcomes for patients with advanced esophageal cancer.
