Authors
Rui Chen, Letao Xu, Alexander H Staudacher, Xing Wang, Ruoxuan Jia, John W Finnie, Xiaoyan Wang, Dawn M Whelan, Michael P Brown, Chun-Xia Zhao
Published in
Science advances. Volume 12. Issue 37. Pages eaed9568. Sep 11, 2026. Epub Sep 11, 2026.
Abstract
The immunosuppressive tumor microenvironment (TME) remains one of the main obstacles that limit responsiveness to immunotherapy. Recently, lipid nanoparticles carrying messenger RNA (mRNA) have emerged as a promising strategy to modulate the immunosuppressive TME, with the ultimate goal of sustaining anticancer immunity of cytotoxic T lymphocytes (CTLs). However, there are challenges with mRNA-based cytokine/chemokine therapies such as the lack of specific targeting, low therapeutic efficacy, and elevated toxicity, raising concerns about their clinical translation. Here, we have developed an antibody-coated lipid nanoparticle (Ab-LNP) delivery system that targets the protein triggering receptor expressed on myeloid cells 2 (TREM2) expressed by tumor-associated macrophages (TAMs). We demonstrate that codelivery of a Toll-like receptor agonist and CXCL9-encoding mRNA encapsulated in our Ab-LNP successfully ameliorates immunosuppression and improves tumor infiltration and activity of CTLs. Further combination with immune checkpoint inhibitors against PD-L1 and CTLA-4 promoted a CTL-favoring immunological environment and durable memory immunity. Our Ab-LNPs targeting TAMs highlight the potential of reprogramming immunosuppressive TME to enhance CTL activity for improved response to cancer immunotherapy.
PMID:
42726873
Bibliographic data and abstract were imported from PubMed on 12 Sep 2026.
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