An Engineered Nano-Bridging Strategy Remodels the Immune Microenvironment of Esophageal Squamous Cell Carcinoma via...

Restoring macrophage-mediated phagocytosis represents a promising strategy for enhancing antitumor innate immunity. However, the highly immunosuppressive tumor immune microenvironment (TIME) of esophageal squamous cell carcinoma (ESCC) limits macrophage infiltration, impairs effector function, and constrains durable responses to immunotherapy. Here, we developed a multifunctional nanoplatform, HA1@diABZI-HMGB1, integrating the ESCC-targeting aptamer HA1, the damage-associated molecular pattern protein HMGB1, and the STING agonist diABZI to remodel the TIME through coordinated immune regulation. In this system, HA1 was designed to improve tumor-cell recognition and tumor-site accumulation, whereas HMGB1 was introduced to promote macrophage-tumor cell interaction and facilitate phagocytic engagement. Meanwhile, intracellular delivery of diABZI activated STING signaling, enhanced proinflammatory cytokine production, and promoted the repolarization of tumor-associated macrophages toward an M1-like phenotype. In ESCC models, HA1@diABZI-HMGB1 enhanced macrophage phagocytosis, reduced M2-like macrophage accumulation, increased dendritic-cell maturation, promoted cytotoxic T-lymphocyte infiltration, and suppressed tumor progression without apparent systemic toxicity. Mechanistically, this integrated strategy combined tumor-targeted anchoring, immune-cell bridging, and innate immune activation within a single nanosystem. Together, these findings support the potential of this nanoplatform to remodel the ESCC immune microenvironment at the preclinical level and provide a basis for further investigation of macrophage-centered immunomodulatory strategies.