2. Academic Validation
  3. Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors

Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors

  • Cell Rep. 2026 Mar 24;45(3):117035. doi: 10.1016/j.celrep.2026.117035.
Yi Wang 1,  Chao Huang 2,  Guoxin Cai 3,  Massimo Andreatta 4,  Armand Kurum 5,  Yang Zhao 6,  Bing Feng 1,  Min Gao 7,  Santiago J Carmona 4,  Zhan Zhou 3,  Cheng Sun 8,  Yugang Guo 9,  Li Tang 10
Affiliations

Affiliations

  • 1 Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland.
  • 2 State Key Laboratory of Immune Response and Immunotherapy, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei 230027, China.
  • 3 Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China.
  • 4 Department of Oncology, University of Lausanne, 1011 Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • 5 Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland.
  • 6 Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland.
  • 7 Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China.
  • 8 State Key Laboratory of Immune Response and Immunotherapy, Anhui Province Key Laboratory of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of University of Science and Technology of China (USTC), University of Science and Technology of China, Hefei 230027, China. Electronic address: [email protected].
  • 9 Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland; Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou 310058, China; Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou 311113, China; Jinhua Institute of Zhejiang University, Jinhua 321299, China. Electronic address: [email protected].
  • 10 Institute of Bioengineering, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Institute of Materials Science & Engineering, EPFL, 1015 Lausanne, Switzerland. Electronic address: [email protected].
PMID: 41758652 DOI: 10.1016/j.celrep.2026.117035
Abstract

Natural killer (NK) cells, a type of potent cytotoxic lymphocyte, are particularly promising for the treatment of cancers that lose or downregulate major histocompatibility complex class I (MHC class I) expression to evade T cell-mediated immunotherapy. However, the hostile and immunosuppressive tumor microenvironment (TME) greatly hinders the function of tumor-infiltrating NK cells, thus limiting the therapeutic efficacy. Here, we show a fusion protein of interleukin 21 (IL-21-Fc) that safely and effectively reprograms NK cell metabolism and restores their effector function in vivo. IL-21-Fc synergizes with IL-15 superagonist (IL-15SA) or adoptive NK cell transfer to eradicate MHC class I-deficient tumors and confer durable protection across multiple murine models. Mechanistically, we uncover that IL-21-Fc enhances NK cell effector function by upregulating glycolysis in a Lactate Dehydrogenase A (LDHA)-dependent manner. This study reveals LDHA-dependent metabolic reprogramming as a key axis for NK cell rejuvenation and positions IL-21-Fc as a promising, clinically translatable strategy to overcome TME-mediated suppression in solid tumors.

Keywords

CP: cancer; CP: metabolism; LDHA; MHC class I-deficient tumor; NK cell exhaustion; NK cell therapy; cancer immunotherapy; glycolysis; immunometabolism; interleukin 21.

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