Metabolic reinvigoration of NK cells by IL-21 enhances immunotherapy against MHC class I-deficient solid tumors
Year: 2026
Type: article
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.
Source: Cell Reports
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Anna Fuller Fund, Massachusetts Institute of Technology, University of California Berkeley, Stiftelsen Kristian Gerhard Jebsen, XtalPi, École Polytechnique Fédérale de Lausanne, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Natural Science Foundation of China, Chinese Academy of Sciences, China Scholarship Council, Université de Lausanne, Swiss Cancer Research Foundation, Swiss Institute of Bioinformatics, Horizon 2020 Framework Programme, HORIZON EUROPE Framework Programme, European Research Council, Natural Science Foundation of Anhui Province, National Key Research and Development Program of China, Shenzhen Science and Technology Innovation Program, H2020 Marie Skłodowska-Curie Actions, Natural Science Foundation of Zhejiang Province
Awards: G1595953743, G2045293885, G2322800720, G3154884412, 代谢增强型肿瘤浸润淋巴细胞治疗实体瘤关键技术研发, G392358020, Alleviating T cell exhaustion in tumors using cytokine-secreting CAR-T cells, G4777486152, Reprograming tumor immune infiltration by targeted delivery of chemokines, G4966013024, G5060296022, G6086173739, Exploiting regulatory circuits guiding tissue context- and metabolism-dependent differentiation program of T cell exhaustion in tumors and chronic viral infection, G8407653081, G8770808336, G8989282095
OpenAlex ID: W7131661920