A bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses

Ying Huang; Geng Qin; TingTing Cui; Chuanqi Zhao; Jinsong Ren; Xiaogang Qu

doi:10.1038/s41467-023-40345-3

A bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses

Nat Commun. 2023 Aug 2;14(1):4647. doi: 10.1038/s41467-023-40345-3.

Authors

Ying Huang^{1

2}, Geng Qin^{3

4}, TingTing Cui^{1

2}, Chuanqi Zhao^{5

6}, Jinsong Ren^{1

2}, Xiaogang Qu^{7

8}

Affiliations

¹ Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China.
² School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China.
³ Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China. qingengjl@sohu.com.
⁴ School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China. qingengjl@sohu.com.
⁵ Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China. chuanqizhao12@yahoo.com.
⁶ School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China. chuanqizhao12@yahoo.com.
⁷ Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, 130022, P. R. China. xqu@ciac.ac.cn.
⁸ School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China. xqu@ciac.ac.cn.

Abstract

Lack of sufficient cytotoxic T lymphocytes (CD8⁺ T cells) infiltration and dysfunctional state of CD8⁺ T cells are considered enormous obstacles to antitumor immunity. Herein, we construct a synergistic nanoplatform to promote CD8⁺ T cell infiltration in tumors while restoring T cell function by regulating methionine metabolism and activating the STING innate immune pathway. The CRISPR/Cas9 system down-regulates the methionine transporter SLC43A2 and restricts the methionine uptake by tumor cells, thereby relieving the methionine competition pressure of T cells; simultaneously, the released nutrition metal ions activate the cGAS/STING pathway. In this work, the described nanoplatform can enhance the effect of immunotherapy in preclinical cancer models in female mice, enhancing STING pathway mediated immunity and facilitating the development of amino acid metabolic intervention-based cancer therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes*
CRISPR-Cas Systems
Female
Immunity
Immunotherapy
Methionine / metabolism
Mice
Neoplasms* / drug therapy
Neoplasms* / therapy

Substances

Methionine