Modulation of Tumor Microenvironment via Antibody Mediated Precision Delivery of CpG to Myeloid Cell

CpG oligodeoxynucleotides (CpG ODNs) are short, synthetically produced DNA molecules that serve as classic agonists of Toll-like receptor 9 (TLR9). They are known for their ability to combat infection, alleviate allergic responses, and inhibit tumor growth. However, free CpG is rapidly degraded by nucleases, distributes poorly, and accumulates minimally in tumors. To overcome these limitations, CpG was tethered to tumor-associated antigens or antibodies that engage Fcγ receptors on immune cells in previous studies. Here we redirected CpG toward myeloid cells via SIRPα, an innate immune checkpoint expressed in dendritic cells and macrophages that transmits “don’t-eat-me” signals upon binding tumor-expressed CD47. The conjugate potently matured bone marrow-derived dendritic cells in vitro and, after simple intraperitoneal delivery, safely suppressed tumor growth in vivo. This myeloid-targeted CpG platform broadens the design space for TLR9 agonists and offers an off-the-shelf strategy for integrating innate and adaptive immunity against cancer.