Bispecific Macrophage Nano-Engager Couples Dual Checkpoint Blockade with Stimulator of Interferon Genes Activation to Potentiate Antitumor Immunity.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 42165513.
- Also identified by DOI 10.1021/acsnano.6c01144.
- No licence information is recorded for this record.
- Because redistribution is not established, this page shows the abstract only. Follow the links below for the full text.
Abstract
The immunosuppressive tumor microenvironment, characterized by impaired antigen presentation, "don't eat me" signaling, and T-cell exhaustion, challenges effective cancer immunotherapy. Conventional T-cell-redirecting bispecific engagers (BiTEs) show limited efficacy in solid tumors because of poor T-cell infiltration, rapid clearance, and dose-limiting cytokine release associated with the CD3 agonism. Therefore, we aimed to enhance macrophage-mediated tumor clearance and T-cell priming by developing a bispecific macrophage nanoengager (nanoBIME) that integrates dual immune checkpoint blockade (anti-SIRPα and anti-PD-L1) with STING-agonist delivery (SR717) in a single poly(lactic-<i>co</i>-glycolic acid) nanocarrier (BIS-PLGA-NP@SR717). BIS-PLGA-NP@SR717 exhibited uniform nanoscale features, efficient SR717 encapsulation, and stable dual-antibody conjugation, enabling systemic delivery with sustained intracellular release. Dual-ligand presentation markedly enhanced receptor binding and nanoparticle uptake in macrophages and PD-L1-expressing tumor cells. BIS-PLGA-NP@SR717 synergistically promoted macrophage phagocytosis, repolarized tumor-associated macrophages toward an M1 phenotype, enhanced dendritic cell maturation, and CD8<sup>+</sup> T-cell activation; additionally, it elevated granzyme B, perforin, and IFN-γ production, resulting in robust T-cell-dependent tumor cell killing. In CT26 tumor-bearing mice, BIS-PLGA-NP@SR717 achieved superior tumor accumulation, deep intratumoral penetration, and dose-dependent tumor regression with minimal systemic toxicity. Transcriptomic profiling further revealed the coordinated activation of phagosome-related pathways, antigen presentation, STING/IFN pathways, chemokine signaling, and T-cell receptor engagement. Collectively, BIS-PLGA-NP@SR717 represents an integrated, multiaxis immunotherapeutic nanoplatform that synchronizes innate activation, macrophage remodeling, and T-cell effector functions. Its modular architecture provides a versatile framework for next-generation immunotherapies for solid tumors.