Targeting tumor-associated macrophages using mRNA lipid nanoparticles for cytotoxic T lymphocyte-mediated cancer immunotherapy.

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.