2. Academic Validation
  3. Microbial metabolite FAD mobilizes adipocyte lipid remodeling to enhance cancer immunotherapy efficacy

Microbial metabolite FAD mobilizes adipocyte lipid remodeling to enhance cancer immunotherapy efficacy

  • Cell Metab. 2026 Mar 3;38(3):565-581.e5. doi: 10.1016/j.cmet.2025.12.012.
Tianying Tong 1,  Xiaowen Huang 1,  Lingxi Li 1,  Muni Hu 1,  Xiaoqiang Zhu 1,  Beiyao Zhu 2,  Yanru Ma 1,  Lijun Ning 1,  Yi Jiang 1,  Yue Zhang 1,  Yilu Zhou 1,  Zhenyu Wang 1,  Jinmei Ding 1,  Ying Zhao 1,  Baoqin Xuan 1,  Youwei Zhang 3,  Xiuying Xiao 4,  Jing-Yuan Fang 1,  Jie Hong 5,  Yan Yin 6,  Fenglin Liu 7,  Haoyan Chen 8
Affiliations

Affiliations

  • 1 State Key Laboratory of Systems Medicine for Cancer, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China.
  • 2 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
  • 3 Department of Medical Oncology, Xuzhou Central Hospital, Clinical School of Xuzhou Medical University, Xuzhou 221009, China.
  • 4 Department of Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
  • 5 State Key Laboratory of Systems Medicine for Cancer, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China. Electronic address: [email protected].
  • 6 Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital of China Medical University, Shenyang 110001, China. Electronic address: [email protected].
  • 7 Second Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Medical Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: [email protected].
  • 8 State Key Laboratory of Systems Medicine for Cancer, Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, Renji Hospital, Shanghai Cancer Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China. Electronic address: [email protected].
PMID: 41570815 DOI: 10.1016/j.cmet.2025.12.012
Abstract

Crosstalk between gut microbiota and adipose tissue critically shapes immunotherapy responses in patients with Cancer. An obesity-associated microbial signature enriched in riboflavin-producing taxa was identified, along with increased microbial riboflavin biosynthesis pathway and elevated levels of flavin adenine dinucleotide (FAD), in obese responders to immune checkpoint blockade (ICB). In diet-induced obese (DIO) mice, fecal microbiota transplantation (FMT), administration of Lachnospiraceae bacterium, or FAD supplementation significantly enhanced the therapeutic efficacy of anti-PD-1 therapy. These interventions increased the cytotoxicity of tumor-infiltrating CD8+ T cells via mesenteric adipocyte-driven synthesis of polyunsaturated fatty acids (PUFAs). Inhibiting fatty acid desaturase 2 (FADS2) eliminated the benefits of FAD, underscoring a critical role for adipocyte-intrinsic lipid remodeling in mediating immune responses. Clinically, elevated systemic levels of PUFAs, particularly docosahexaenoic acid (DHA), were positively correlated with intratumoral CD8+ T cell infiltration and favorable immunotherapy outcomes. Dietary DHA supplementation improved ICB responses in lean mice. This study highlights that a microbiota-adipose axis shapes antitumor immunity, enabling potential personalized metabolic and microbial immunotherapy strategies.

Keywords

adipocyte; gut microbiota; immunotherapy; microbial metabolite; obesity; unsaturated fatty acids.

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