Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds

Bao-cun Zhang (), Marlene F. Laursen, Lili Hu, Hossein Hazrati, Ryo Narita, Lea S. Jensen, Aida S. Hansen, Jinrong Huang, Yan Zhang, Xiangning Ding, Maimaitili Muyesier, Emil Nilsson, Agnieszka Banasik, Christina Zeiler, Trine H. Mogensen, Anders Etzerodt, Ralf Agger, Mogens Johannsen, Emil Kofod-Olsen, Søren R. Paludan () and Martin R. Jakobsen ()
Additional contact information
Bao-cun Zhang: Aarhus University
Marlene F. Laursen: Aalborg University
Lili Hu: Aarhus University
Hossein Hazrati: Aarhus University
Ryo Narita: Aarhus University
Lea S. Jensen: Aarhus University
Aida S. Hansen: Aarhus University
Jinrong Huang: University of Copenhagen
Yan Zhang: Aarhus University
Xiangning Ding: Aarhus University
Maimaitili Muyesier: Aarhus University
Emil Nilsson: Aarhus University
Agnieszka Banasik: Aalborg University
Christina Zeiler: Aalborg University
Trine H. Mogensen: Aarhus University
Anders Etzerodt: Aarhus University
Ralf Agger: Aalborg University
Mogens Johannsen: Aarhus University
Emil Kofod-Olsen: Aalborg University
Søren R. Paludan: Aarhus University
Martin R. Jakobsen: Aarhus University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract The cGAS-STING pathway plays a crucial role in anti-tumoral responses by activating inflammation and reprogramming the tumour microenvironment. Upon activation, STING traffics from the endoplasmic reticulum (ER) to Golgi, allowing signalling complex assembly and induction of interferon and inflammatory cytokines. Here we report that cGAMP stimulation leads to a transient decline in ER cholesterol levels, mediated by Sterol O-Acyltransferase 1-dependent cholesterol esterification. This facilitates ER membrane curvature and STING trafficking to Golgi. Notably, we identify two cholesterol-binding motifs in STING and confirm their contribution to ER-retention of STING. Consequently, depletion of intracellular cholesterol levels enhances STING pathway activation upon cGAMP stimulation. In a preclinical tumour model, intratumorally administered cholesterol depletion therapy potentiated STING-dependent anti-tumoral responses, which, in combination with anti-PD-1 antibodies, promoted tumour remission. Collectively, we demonstrate that ER cholesterol sets a threshold for STING signalling through cholesterol-binding motifs in STING and we propose that this could be exploited for cancer immunotherapy.

Date: 2024
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DOI: 10.1038/s41467-024-47046-5

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