Agonists for cytosolic bacterial receptor ALPK1 induce antitumour immunity

  • Nature. 2026 Feb;650(8100):242-250. doi: 10.1038/s41586-025-09828-9.
Xiaoying Tian  #  1  2 ,  Jiaqi Liu  #  1  2 ,  Yuxi Li  2 ,  Yupeng Wang  2 ,  Yuanhanyu Luo  2 ,  Huabin He  2 ,  Yang She  2 ,  Yan Ma  2 ,  Jingjin Ding  2  3 ,  Ping Zhou  2  4 ,  Chao Li  2 ,  Feng Shao  5  6  7  8  9  10
Affiliations
  • 1. Graduate School of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, P. R. China.
  • 2. National Institute of Biological Sciences, Beijing, P. R. China.
  • 3. Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P. R. China.
  • 4. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, P. R. China.
  • 5. National Institute of Biological Sciences, Beijing, P. R. China. [email protected].
  • 6. Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, P. R. China. [email protected].
  • 7. Research Unit of Pyroptosis and Immunity, Chinese Academy of Medical Sciences, Beijing, P. R. China. [email protected].
  • 8. Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, P. R. China. [email protected].
  • 9. Changping Laboratory, Beijing, P. R. China. [email protected].
  • 10. New Cornerstone Science Laboratory, Shenzhen, P. R. China. [email protected].
  • # Contributed equally.
PMID: 41372408 DOI: 10.1038/s41586-025-09828-9
Abstract

Targeting innate immunity holds promise in Cancer Immunotherapy, particularly in improving checkpoint inhibitors. However, the use of agonists of the promising innate receptors TLRs and STING1-4 is facing challenges. Here we examined the antitumour function of the α-kinase 1 (ALPK1) receptor for Bacterial ADP-heptose (ADP-Hep)5-7. Treatment of mice with ADP-Hep induced multiple proinflammatory factors including CXCL10 and CCL2, and stimulated Alpk1-dependent antitumour immunity. Mice bearing a gain-of-function ALPK1(T237M) disease variant8 also rejected grafted tumours. Using medicinal chemistry, we identified a more potent analogue, UDSP-Hep. In contrast to ADP-Hep, UDSP-Hep distinguished Alpk1 polymorphism, which correlates with mouse susceptibility to bacteria-associated colitis9-12. UDSP-Hep exhibited a stronger Alpk1-mediated antitumour effect and synergized with checkpoint inhibitors. The effect required CD8+ T cells, dendritic cells (DCs) and macrophages, and was sensitive to antibodies that block CXCL10 or CCL2 function. ALPK1 agonists activated DCs for cross-presentation, promoting tumour-specific T cell expansion in the tumour-draining lymph nodes. ALPK1 has wider expression than STING in non-immune cells with a distinct inflammatory signature. UDSP-Hep is differentiated from STING agonists in stimulating tumour-cell antigen presentation, macrophage-DC cross-priming and protective memory T cell differentiation, and it does not induce T cell Apoptosis. Our study elucidates the antitumour effect of ALPK1 agonism and suggests the potential of ALPK1 agonists in Cancer Immunotherapy.

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