Immune exhaustion in esophageal cancer: interferon pathway dysregulation and neoadjuvant therapy response

Esophageal cancer (EC) is an aggressive malignancy with poor survival despite advances in multimodal treatment. Local control of the disease is possible with chemotherapeutic, radiotherapeutic, and chemoradiotherapeutic neoadjuvant therapies, although treatment resistance and recurrence are common, and disease progression continues. Several studies show that the so-called immune exhaustion in the tumor microenvironment (TME) is the most significant cause of failure of the aforementioned treatments. Specifically, dysregulated interferon (IFN) signaling may have paradoxical effects in EC, promoting antitumor immune activation in some contexts while contributing to immune suppression, checkpoint upregulation, and tumor adaptation when chronically activated. This review examines whether IFN pathway dysregulation, particularly involving IER2 and IFNGR1, may contribute to immune exhaustion and influence neoadjuvant therapy response. In particular, we examine the role of the interferon-related genes (IRGs) in the immediate early response 2 (IER2) and interferon gamma receptor 1 (IFNGR1) in the mechanistic clinical role of neoadjuvant therapies. It includes radiotherapy, chemotherapy, and immune remodeling. Evidence of persistent IFN signaling T cell exhaustion, immune checkpoint upregulation, the phenomenon of adaptive resistance and the lack of therapeutically adequate sustained efficacy are analyzed. Finally, we show how the changes in the tumor immune microenvironment (TIME) caused by the neoadjuvant therapy (NAT) induced IFN activation. In particular, we examine the changes in the cross-presentation of immunogenic cells, cytokines, cytokine receptors, and exhaustion. This paper outlines a structure connecting IFN-induced immune exhaustion with responses to neoadjuvant therapy in EC, integrating epidemiology, molecular crossroads, and innovative translational research. To conclude, we examine prospective treatment efforts to address immune exhaustion through IFN pathway adjustment, strategic combination therapies, and biomarkers to refine patient stratification. A clearer understanding of context-dependent IFN signaling may support biomarker-guided neoadjuvant strategies and rational combination therapies in EC.