Optogenetic engineering of STING signaling allows remote immunomodulation to enhance cancer immunotherapy

Yaling Dou, Rui Chen, Siyao Liu, Yi-Tsang Lee, Ji Jing, Xiaoxuan Liu, Yuepeng Ke, Rui Wang, Yubin Zhou () and Yun Huang ()
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Yaling Dou: Texas A&M University
Rui Chen: Texas A&M University
Siyao Liu: Texas A&M University
Yi-Tsang Lee: Texas A&M University
Ji Jing: Texas A&M University
Xiaoxuan Liu: Texas A&M University
Yuepeng Ke: Texas A&M University
Rui Wang: Texas A&M University
Yubin Zhou: Texas A&M University
Yun Huang: Texas A&M University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The cGAS-STING signaling pathway has emerged as a promising target for immunotherapy development. Here, we introduce a light-sensitive optogenetic device for control of the cGAS/STING signaling to conditionally modulate innate immunity, called ‘light-inducible SMOC-like repeats’ (LiSmore). We demonstrate that photo-activated LiSmore boosts dendritic cell (DC) maturation and antigen presentation with high spatiotemporal precision. This non-invasive approach photo-sensitizes cytotoxic T lymphocytes to engage tumor antigens, leading to a sustained antitumor immune response. When combined with an immune checkpoint blocker (ICB), LiSmore improves antitumor efficacy in an immunosuppressive lung cancer model that is otherwise unresponsive to conventional ICB treatment. Additionally, LiSmore exhibits an abscopal effect by effectively suppressing tumor growth in a distal site in a bilateral mouse model of melanoma. Collectively, our findings establish the potential of targeted optogenetic activation of the STING signaling pathway for remote immunomodulation in mice.

Date: 2023
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DOI: 10.1038/s41467-023-41164-2

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