Work

The Tango of cGAS-STING and Phagocytosis in Disease: From Molecular Mechanisms to Pharmacological Targeting

Year: 2026

Type: review

Abstract: The cGAS-STING pathway is a central cytosolic DNA sensor that orchestrates innate immune responses beyond type I interferons, including autophagy, senescence, metabolism, and cell death. Phagocytosis-essential for clearing pathogens, debris, and apoptotic bodies-critically bridges innate and adaptive immunity. This review examines the bidirectional, context-dependent interplay between these fundamental processes and highlights how nanotechnology is uniquely positioned to exploit this crosstalk for therapeutic gain. We delineate four paradigms: STING activation upstream induces phagocytosis in lung inflammation, sepsis, spinal cord injury, cancer, and viral infection; phagocytosis initiates STING by delivering immunogenic cargo; positive feedback loops amplify antitumor immunity; and STING can suppress phagocytosis in obesity-driven adipose inflammation. Importantly, this axis exerts opposing regulatory effects across disease settings, being protective or pathogenic, synergistic or antagonistic, depending on cell type, stimulus, and pathological context. We further synthesize advanced nanoplatforms-biomimetic nanoparticles, hybrid membrane vesicles, DNA nanodevices, lymph node-targeted nanovaccines, and "Trojan horse" nanocapsules-engineered to co-deliver STING agonists, phagocytosis checkpoint inhibitors, and immunogenic cargo. These nanotherapies enhance antitumor and antimicrobial defense, resolve inflammation, and overcome barriers such as the blood-brain barrier. By integrating mechanism with nanobiotechnology, this review provides a conceptual framework for the cGAS -STING-phagocytosis network and a roadmap for next-generation nanomedicines treating cancer, infection, neurodegeneration, and inflammatory disorders.

Source: Drug Design Development and Therapy

DOI: 10.2147/dddt.s650641

Authors: Hongquan Wang, Jinxia Chen, Zhiji Wang, Fan Wu