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.