Unveiling the key roles in esophageal cancer drug resistance from a genetic perspective: the interplay between cytokines and immune cell phenotypes.

Background: Esophageal cancer (EC) is a common malignant tumor, often diagnosed in its late stages due to the subtlety of early symptoms. Traditional chemotherapy inflicts significant harm on the organism; however, the emergence of targeted and immune therapies has conferred considerable survival advantages for patients with EC. However, the prolonged exposure of immune cells to the tumor microenvironment (TME) results in functional deterioration, thereby causing drug resistance and notably diminishing the therapeutic outcomes. Therefore, it is necessary to gain an in-depth understanding of the immune microenvironment of EC to find ways to overcome the development of resistance.

Objective: This study aimed to explore the causal relationships between cytokines, immune cell phenotypes, and the development of EC, with particular emphasis on their role in tumor progression and drug resistance. Using Mendelian randomization, we sought to identify key immune-related factors implicated in EC pathogenesis and evaluate their potential as therapeutic targets for overcoming resistance to treatment.

Results: Through univariable MR, we found that two cytokines and twenty-two immune cell phenotypes are significantly associated with the incidence of EC. Further bidirectional MR analysis indicated interactions between two cytokines and five immune cells. Lastly, two-step MR analysis showed that there are mediating pathways in both directions between cytokines and immune cell phenotypes.

Conclusion: This research deepens the understanding of the mechanisms underlying the interactions between key cytokines and immune cells associated with the onset of EC. The research provides new insights into the issue of drug resistance within the esophageal cancer TME and offers novel perspectives for the development of targeted and immune-based therapies for EC.