Nanotechnology-enabled immunomodulation in esophageal cancer: targeting the tumor microenvironment to overcome therapeutic barriers

Abstract

Esophageal cancer is a highly aggressive malignancy with a notoriously poor prognosis. While immunotherapy, particularly immune checkpoint blockade (ICB), has revolutionized oncology, its clinical efficacy in esophageal cancer is severely limited by primary and acquired resistance. This resistance is fundamentally driven by a deeply immunosuppressive tumor microenvironment (TME), characterized by severe hypoxia, acidosis, a dense extracellular matrix (ECM), and an abundance of immunosuppressive populations such as M2-like tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Consequently, the esophageal TME manifests as an immunologically “cold” phenotype that actively excludes and exhausts effector T cells. Nanotechnology has emerged as a transformative paradigm to dismantle these physiological and immunological barriers. This review provides a comprehensive analysis of nanotechnology-enabled immunomodulation strategies designed to remodel the esophageal TME. We systematically explore state-of-the-art targeted nanoplatforms and highlight their specific mechanisms in TME reprogramming, including alleviating hypoxia and acidosis, repolarizing TAMs, restoring dendritic cell (DC) function, and inducing immunogenic cell death (ICD) and ferroptosis. Furthermore, we evaluate synergistic strategies that combine rationally designed nanomedicines with diverse immunotherapeutic modalities to overcome resistance. By facilitating the crucial transition from “cold” to “hot” tumors, nanotechnology offers promising potential to amplify antitumor immunity and may contribute to improving clinical outcomes in esophageal cancer.