A BCG hydrogel enables localized NOD2/STING activation to overcome resistance to immune checkpoint blockade - PubMed
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- #BCG hydrogel
- #immune checkpoint resistance
- #tumor microenvironment
- Resistance to immune checkpoint blockade (ICB) often occurs in immunologically cold tumors with suppressive myeloid cells.
- A NOD2high tumor-associated macrophage (TAM) subset linked to inflammatory and immune-activating programs was identified in colorectal cancer via single-cell transcriptomic analysis.
- An injectable manganese-containing alginate hydrogel encapsulating polyarginine-functionalized Bacillus Calmette-Guérin (MHY@PBCG) was engineered for sustained intratumoral delivery and localized coactivation of NOD2 and STING signaling in TAMs.
- Polyarginine enhanced BCG uptake by macrophages, while Mn2+ stabilized the hydrogel and amplified STING activation.
- Local administration of MHY@PBCG reprogrammed TAMs toward an M1-like phenotype, increased inflammatory cytokine and interferon programs, converted cold tumors into immune-inflamed lesions, and restored responsiveness to anti-PD1 therapy in multiple models.
- Coordinated NOD2/STING activation established a self-reinforcing inflammatory circuit linking macrophage reprogramming to downstream T cell-mediated antitumor immunity.
- This localized biomaterial strategy offers a way to overcome checkpoint resistance by macrophage-centered remodeling of the tumor microenvironment.