Targeted mRNA Nanoparticles Reprogram Macrophages to Boost Antitumor Immunity

Immune checkpoint therapy has transformed the treatment landscape for solid tumors over the past decade. Inhibitors targeting PD-1, PD-L1, and CTLA-4 have enabled some patients with advanced cancer to achieve long-term survival. However, substantial limitations remain: only approximately 20%–30% of patients with solid tumors derive significant clinical benefit from these therapies. Most tumors establish a highly immunosuppressive tumor microenvironment that prevents immune cells from infiltrating the tumor or impairs their cytotoxic activity even after they arrive.

Overcoming this suppressive environment and converting immunologically “cold” tumors into “hot” tumors that can be effectively attacked by immune cells remains a central challenge in cancer immunotherapy.

Lipid nanoparticle–mRNA technology, widely recognized following the success of COVID-19 mRNA vaccines, is considered a promising tool for remodeling the tumor microenvironment. However, conventional mRNA-based cytokine and chemokine therapies face several translational barriers, including a lack of cell-specific targeting, limited overall therapeutic efficacy, and the risk of systemic toxicity. These challenges have hindered their further clinical development.

A preclinical study published in Science Advances, entitled “Targeting Tumor-Associated Macrophages Using mRNA Lipid Nanoparticles for Cytotoxic T Lymphocyte-Mediated Cancer Immunotherapy,” presents an innovative solution. The researchers coated lipid nanoparticles with a targeting antibody, enabling them to selectively locate tumor-associated macrophages (TAMs), which act as accomplices to tumor progression. By delivering therapeutic cargo directly into these cells, the nanoparticles reprogrammed the macrophages and helped reverse local immunosuppression.

Dual Delivery Reprograms Macrophages and Recruits Cytotoxic T Cells

Macrophages normally function as the immune system’s scavengers, clearing pathogens, cellular debris, and damaged cells. Under persistent signals from the tumor microenvironment, however, large numbers of macrophages can undergo phenotypic conversion and begin helping tumors evade immune surveillance.

These immunosuppressive macrophages express high levels of triggering receptor expressed on myeloid cells 2 (TREM2) on their surface. The researchers used TREM2 as a targeting marker and conjugated anti-TREM2 antibodies to the surface of lipid nanoparticles. This modification enabled the nanoparticles to selectively recognize tumor-associated macrophages and deliver their therapeutic payload directly into the target cells.

After entering the macrophages, the nanoparticles released two functional components simultaneously. The first was mRNA encoding the chemokine CXCL9. Acting as a chemical recruitment signal, CXCL9 attracts tumor-killing CD8⁺ cytotoxic T lymphocytes (CTLs) into the tumor.

The second component was resiquimod, an agonist of Toll-like receptors 7 and 8. Resiquimod reprogrammed macrophages from an immunosuppressive phenotype into a proinflammatory, antitumor phenotype.

Figure 1. Schematic illustration of TAM-targeted resiquimod mRNA-CXCL9 LNPs for cancer immunotherapy. (Chen R, et al., 2026)

Through this dual-delivery strategy, a single nanoparticle system accomplished two complementary tasks: converting existing tumor-supporting macrophages into immune-stimulatory cells and recruiting cytotoxic T cells into the tumor. Together, these effects weakened the immunosuppressive defenses from within the tumor microenvironment.

Promising Results in a Triple-Negative Breast Cancer Model

In a mouse model of 4T1 triple-negative breast cancer, the TREM2-targeted, antibody-coated lipid nanoparticles, designated T-RmRNA LNPs, produced encouraging experimental results.

Following treatment, the proportion of immunosuppressive tumor-associated macrophages in tumor tissue decreased by 63.2%, while intratumoral CXCL9 protein levels increased fourfold. Both the number of infiltrating CD8⁺ cytotoxic T cells and their tumor-killing activity increased within the tumor microenvironment. Together, these immune changes resulted in moderate inhibition of tumor growth.

The researchers also combined the nanoparticle treatment with immune checkpoint inhibitors targeting PD-L1 and CTLA-4. This combination further increased the infiltration of helper T cells and cytotoxic T lymphocytes into the tumors. An increased proportion of central memory CD8⁺ T cells was also observed in the tumor-draining lymph nodes. These memory cells may help the immune system establish durable antitumor immune memory.

Importantly, however, the combination regimen did not produce an additional improvement in tumor growth inhibition in this animal model. Although the immune landscape became more favorable, the immunological changes did not translate into an additive antitumor effect under the conditions tested.

From Nonspecific Delivery to Cell-Selective Immunomodulation

This study advances mRNA-LNP technology from a largely nonspecific delivery approach toward cell-selective therapeutic delivery. Previous mRNA immunotherapies have struggled to restrict their activity to a particular cell population within the tumor microenvironment. In contrast, the antibody-modified nanoparticles enabled targeted delivery to TREM2-positive tumor-associated macrophages while simultaneously promoting chemokine expression and macrophage reprogramming.

Rather than directly killing tumor cells, this strategy targets the immunosuppressive cells that support tumor growth. By altering the immune state of the tumor microenvironment, the treatment creates more favorable conditions for subsequent immune attack. The approach is therefore closely aligned with current efforts to convert immunologically cold tumors into hot tumors that are more responsive to immunotherapy.

The researchers noted that a major challenge in cancer immunotherapy is often not the immune system’s inability to kill tumor cells. Instead, the tumor microenvironment prevents immune cells from reaching the tumor or functioning effectively. This study addresses that problem by attempting to reshape the immune environment from within the tumor.

Nevertheless, the work remains a proof-of-concept preclinical study conducted at the cellular and animal levels. The reductions in immunosuppressive macrophages, increases in CXCL9 expression, and activation of T cells were all observed in mouse models. The absence of additional tumor suppression when the nanoparticles were combined with immune checkpoint inhibitors also indicates that the optimal clinical setting and most effective combination strategy require further investigation.

Although histopathological examinations suggested that the treatment was well tolerated in mice, the potential for systemic inflammation caused by mRNA and Toll-like receptor agonists must still be carefully evaluated. Long-term in vivo toxicity also remains unknown.

Despite these limitations, the study demonstrates that engineered nanoparticles can selectively deliver immunomodulatory agents to critical immune cell populations within the tumor microenvironment. The findings provide a promising direction for improving responses to immunotherapy in solid tumors, although substantial additional research will be required before the strategy can be translated into treatment for patients.