2. Academic Validation
  3. MITA/STING-driven CD38 induction in Siglec-Flow macrophages promotes regulatory T cell survival and non-small cell lung cancer progression

MITA/STING-driven CD38 induction in Siglec-Flow macrophages promotes regulatory T cell survival and non-small cell lung cancer progression

  • Dev Cell. 2026 Jan 12:S1534-5807(25)00768-3. doi: 10.1016/j.devcel.2025.12.007.
Zhi-Dong Zhang 1,  Yu-Lin Lin 1,  Han-Yue Zhang 1,  Cong Zuo 1,  Zhong-Lin Zhu 1,  Xing-Yuan Wang 1,  Hao-Yu Duan 1,  Junjie Zhang 1,  Dandan Lin 2,  Bo Zhong 3
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Cancer Center, Renmin Hospital of Wuhan University, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, State Key Laboratory of Metabolism and Regulation in Complex Organisms, State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, Wuhan University, Wuhan 430071, China.
  • 2 Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Cancer Center, Renmin Hospital of Wuhan University, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, State Key Laboratory of Metabolism and Regulation in Complex Organisms, State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
  • 3 Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Cancer Center, Renmin Hospital of Wuhan University, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, State Key Laboratory of Metabolism and Regulation in Complex Organisms, State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, Wuhan University, Wuhan 430071, China; TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: [email protected].
PMID: 41529690 DOI: 10.1016/j.devcel.2025.12.007
Abstract

Stimulator of interferon (IFN) genes (STING, also known as [mediator of IRF3 activation]) is a 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) receptor that activates type I IFN responses to inhibit tumorigenesis in tumor cells. However, STING agonists show limited antitumor clinical efficacy. Here, we demonstrate that STING in macrophages promotes the survival of regulatory T cells (Tregs) and the progression of non-small cell lung Cancer (NSCLC) in KRasG12D autochthonous NSCLC mouse models. Mechanistically, STING-mediated nuclear factor κB (NF-κB) activation upregulates CD38 in Siglec-Flow macrophages to hydrolyze extracellular nicotinamide adenine dinucleotide (NAD) in the tumor microenvironment (TME). Genetic deletion of STING or CD38, or pharmacological CD38 inhibition, restores NAD levels, triggers Treg Apoptosis through the ART2-P2RX7 axis, and enhances antitumor CD8+ T cell responses. Importantly, CD38 inhibition improves the efficacy of low-dose anti-CTLA4 therapy. These findings uncover a previously uncharacterized cGAMP-STING-CD38 axis in macrophages supporting Treg survival and NSCLC progression and highlight potential therapeutic strategies for immune checkpoint blockade (ICB)-resistant cancers.

Keywords

CD38; MITA/STING; NAD; immune checkpoint blockade therapy; macrophage; nicotinamide adenine dinucleotide; non-small cell lung cancer; regulatory T cells; tumor microenvironment.

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