TLR3 agonist nanoscale coordination polymer synergizes with immune checkpoint blockade for immunotherapy of cancer.

ABSTRACT

Immunotherapies including immune checkpoint blockade (ICB) have become integral to treatments for immunogenic tumors by reinvigorating host immune functions to attack tumor cells. However, the clinical applications of ICB are limited by relatively low response rates as well as inherent and acquired resistance in many types of cancer. A potential solution is to selectively deliver immune modulators to tumors to activate the tumor microenvironment (TME) and enhance the therapeutic effect of ICB. Here we report the design of polyinosinic polycytidylic acid (pIC) nanoscale coordination polymer (NCP), pIC@NCP, and its ability to activate tumor-specific immune responses and synergize with ICB for potent antitumor effects. With prolonged blood circulation, facile cell uptake, and triggered release of pIC in acidic TMEs, pIC@NCP shows robust tumor growth inhibition via activation of the endosomal toll-like receptor 3 signaling pathway. The synergistic combination of pIC@NCP and ICB further controls tumor growth in syngeneic mouse models of colorectal cancer and a spontaneous mouse model of prostate cancer. This study highlights the potential of NCP delivery of nucleic acid therapeutics for immune activation and cancer therapy.