Intratumoral adoptive transfer of inflammatory macrophages engineered by co-activating TLR and STING signaling pathways exhibits robust antitumor activity

Abstract

Despite the success of chimeric antigen receptor (CAR) T cells in hematologic malignancies, adoptive cell therapy (ACT) has not been effective in treating solid tumors. Here, we developed an inflammatory macrophage-based ACT to effectively treat solid tumors. We engineered inflammatory macrophages to enhance their antitumor activities, including proinflammatory cytokine secretion and co-stimulatory molecule expression by co-activating toll-like receptor and stimulator of interferon genes signaling pathways. Engineered macrophages maintain an inflammatory phenotype after their adoptive transfer into the anti-inflammatory tumor microenvironment (TME), whereas conventional inflammatory macrophages prepared using interferon-γ treatment are repolarized to an anti-inflammatory phenotype. In a mouse melanoma model, intratumoral adoptive transfer of engineered macrophages showed robust tumor growth inhibition by increasing CD8⁺ T cells in the TME and tumor antigen-specific CD8⁺ T cells in the blood. This study demonstrated that engineered inflammatory macrophages have potential as an effective ACT for treating solid tumors.

Keywords: Cancer immunotherapy; Cell therapy; Inflammatory macrophages; Pattern-recognition receptor signaling pathways; Solid tumors.