Dendritic cell centric nanoengineering couples antigen acquisition and STING activation for cancer immunotherapy.
basic_science · Level V
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- Record sourced from PubMed, PMID 42705236.
- Also identified by DOI 10.1016/j.xcrm.2026.103025.
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Abstract
Stimulator of interferon genes (STING) agonists have shown limited antitumor efficacy, in part because STING activation is not preferentially focused on dendritic cells (DCs), which specialize in cross-priming. We present a DC-centric strategy that synergistically licenses DCs by coordinating CD47-SIRPα checkpoint relief and STING activation via dual ultra-pH-sensitive gating. Mild tumor acidity first unmasks the αCD47 cue to prime antigen acquisition. Following DC-biased uptake, a second acidic gate releases cGAMP to engage STING in antigen-bearing DCs. Functionally, efficacy requires Batf3-dependent cDC1s and CD8<sup>+</sup> T cells, yet is preserved after macrophage depletion. In murine models, this strategy suppresses tumor growth and metastasis with good tolerability, and it retains activity in a humanized cell-line-derived xenograft model established in NSG-SGM3 hosts, supporting activity in a partially reconstituted human immune setting. Together, this work presents a mechanism-guided combination strategy to optimize STING agonist therapy.