TLR7/8 signaling activation enhances the potency of human pluripotent stem cell-derived eosinophils in cancer immunotherapy for solid tumors

  • Exp Hematol Oncol. 2025 Mar 1;14(1):26. doi: 10.1186/s40164-025-00613-y.
Sheng Zhu  #  1 ,  Zhengyang Zhou  #  1 ,  Ruixin Gu  2 ,  Zixin Zhao  1 ,  Yingfeng Zhang  1 ,  Yudi Miao  1 ,  Qi Lei  3 ,  Tianxing Liu  1 ,  Guokai Wang  1 ,  Chenyi Dai  1 ,  Yi Huo  1 ,  Jinghao You  1 ,  Lejun Lv  1 ,  Cheng Li  1  2 ,  Ming Yin  4 ,  Chengyan Wang  5 ,  Hongkui Deng  6  7
Affiliations
  • 1. MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
  • 2. Center for Bioinformatics, Center for Statistical Science, School of Life Sciences, Peking University, Beijing, 100871, China.
  • 3. State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, 100191, China.
  • 4. Beijing Vitalstar Biotechnology, Beijing, 100012, China.
  • 5. MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China. [email protected].
  • 6. MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China. [email protected].
  • 7. State Key Laboratory of Natural and Biomimetic Drugs, School of Basic Medical Sciences, Peking University Health Science Center, Peking University, Beijing, 100191, China. [email protected].
  • # Contributed equally.
PMID: 40025520 DOI: 10.1186/s40164-025-00613-y
Abstract

Background: Efficient tumor T-cell infiltration is crucial for the effectiveness of T-cell-based therapies against solid tumors. Eosinophils play crucial roles in recruiting T cells in solid tumors. Our group has previously generated induced eosinophils (iEOs) from human pluripotent stem cells and exhibited synergistic efficacy with CAR-T cells in solid tumor inhibition. However, administrated eosinophils might influx into inflammatory lungs, posing a potential safety risk. Mitigating the safety concern and enhancing efficacy is a promising development direction for further application of eosinophils.

Methods: We developed a new approach to generate eosinophils with enhanced potency from human chemically reprogrammed induced pluripotent stem cells (hCiPSCs) with the Toll-like Receptor (TLR) 7/8 signaling agonist R848.

Results: R848-activated iEOs (R-iEOs) showed significantly decreased influx to the inflamed lungs, indicating a lower risk of causing airway disorders. Furthermore, these R-iEOs had enhanced anti-tumor functions, preferably accumulated at tumor sites, and further increased T-cell infiltration. The combination of R-iEOs and CAR-T cells suppressed tumor growth in mice. Moreover, the chemo-trafficking signaling increased in R-iEOs, which may contribute to the decreased lung influx of R-iEOs and the increased tumor recruitment of T cells.

Conclusion: Our study provides a novel approach to alleviate the potential safety concerns associated with eosinophils while increasing T-cell infiltration in solid tumors. This finding offers a prospective strategy for incorporating eosinophils to improve CAR-T-cell immunotherapy for solid tumors in the future.

Keywords
Eosinophils; Immunotherapy; Lung influx; Pluripotent stem cells; R848; Safety; Solid tumor; T-cell infiltration; TLR7/8 signaling.
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