@article{5ef22ab3e18a4ccb853e150be3f5fba3,
title = "Tumor-targeted delivery of a STING agonist improves cancer immunotherapy",
abstract = "The cGAS-STING pathway is essential for immune defense against microbial pathogens and malignant cells; as such, STING is an attractive target for cancer immunotherapy. However, systemic administration of STING agonists poses safety issues while intratumoral injection is limited by tumor accessibility. Here, we generated antibody-drug conjugates (ADCs) by conjugating a STING agonist through a cleavable linker to antibodies targeting tumor cells. Systemic administration of these ADCs was well tolerated and exhibited potent antitumor efficacy in syngeneic mouse tumor models. The STING ADC further synergized with an anti-PD-L1 antibody to achieve superior antitumor efficacy. The STING ADC promoted multiple aspects of innate and adaptive antitumor immune responses, including activation of dendritic cells, T cells, natural killer cells and natural killer T cells, as well as promotion of M2 to M1 polarization of tumor-associated macrophages. These results provided the proof of concept for clinical development of the STING ADCs.",
keywords = "ADC, cancer, cGAS, STING, tumor immunity",
author = "Wu, {You Tong} and Yan Fang and Qi Wei and Heping Shi and Huiling Tan and Yafang Deng and Zhiqun Zeng and Jian Qiu and Chuo Chen and Lijun Sun and Chen, {Zhijian J.}",
note = "Funding Information: Author affiliations: a阀mmuneSensor Therapeutics, Dallas, TX 75235; bDepartment of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; cCenter for 阀nflammation Research, University of Texas Southwestern Medical Center, Dallas, TX 75390; dDepartment of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390; and eHHM 阀, Chevy Chase, MD 20815 Author contributions: Y.-t.W., Y.F., J.Q., C.C., L.S., and Z.J.C. designed research; Y.-t.W., Y.F., Q.W., H.S., H.T., Y.D., Z.Z., and L.S. performed research; Y.-t.W., Y.F., Q.W., H.S., H.T., Y.D., Z.Z., L.S., and Z.J.C. analyzed data; and Y.-t.W., Y.F., L.S., and Z.J.C. wrote the paper. Reviewers: K.A.F., University of Massachusetts Medical School; and J.T., The University of North Carolina at Chapel Hill. Competing interest statement: The authors declare a competing interest. The authors have organizational affiliations to disclose, Z.J.C. is a scientific collaborator with Pfizer and 阀mmuneSensor Therapeutics, and a scientific advisor for Brii Biosciences, Genor Biopharma and Drug Farm. C.C. is a scientific advisor for 阀mmuneSensor Therapeutics., Z.J.C. has stock ownership in Brii Biosciences. H.S., L.S., C.C., and Z.J.C. are inventors of US patent 10,336,786. Q.W., H.S., L.S, C.C., and Z.J.C. are inventors of US patent 10,519,188. Y.-t.W., Q.W., H.S., J.Q, L.S., C.C., and Z.J.C. are inventors of US patent 11,033,635. Z.J.C. received research support from Pfizer and 阀mmuneSensor Therapeutics. Funding Information: ACK?OWLED?ME?TS. We thank Dr. Yang-Xin Fu for providing the B16-EGFR and MC38-EGFR cell lines. This work was supported in part by ImmuneSensor Therapeutics. Z.J.C. is an HHMI investigator. Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s).",
year = "2022",
month = dec,
day = "6",
doi = "10.1073/pnas.2214278119",
language = "English (US)",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "49",
}