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Purpose <p>Glioblastoma (GBM), an aggressive brain malignancy with high recurrence rates and suboptimal response to conventional therapies, necessitates novel treatment strategies. Chimeric antigen receptor natural killer (CAR-NK) cell therapy represents a promising immunotherapeutic approach. CSPG4 (chondroitin sulfate proteoglycan 4), a tumor-associated antigen overexpressed in GBM and critically involved in tumor proliferation and metastasis, was investigated as a therapeutic target. This study aimed to evaluate the efficacy of CSPG4-targeted CAR-NK cells in GBM treatment.</p> Methods and results <p>We engineered a second-generation CAR construct incorporating the CSPG4-specific scFv 763.74, a CD8 transmembrane domain, and intracellular co-stimulatory/activation domains from CD28 and CD3ζ. The resulting CAR-NK cells were tested for anti-tumor activity in vitro and in vivo. Results demonstrated that CSPG4-directed CAR-NK cells selectively recognized and lysed CSPG4-positive GBM cells, significantly suppressing tumor growth in preclinical models compared to control NK cells. Mechanistic studies confirmed that cytotoxicity was mediated through specific CSPG4 antigen engagement.</p> Conclusion <p>CSPG4-targeted CAR-NK cells exhibit potent anti-GBM activity, highlighting their potential as a novel immunotherapy. These findings provide a robust preclinical foundation for advancing CSPG4-directed CAR-NK cell therapy into clinical trials, addressing the urgent need for effective treatments in GBM management.</p>

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Targeting CSPG4 enhances the anti-tumor activity of CAR-NK cells for glioblastoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月28日

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  • Qi Xiong,
  • Beibei Yin,
  • Hong Jiang,
  • Yusha Qiu,
  • Gang Shi,
  • Jia Xu,
  • Tong Xu,
  • Hongxin Deng

摘要

Purpose

Glioblastoma (GBM), an aggressive brain malignancy with high recurrence rates and suboptimal response to conventional therapies, necessitates novel treatment strategies. Chimeric antigen receptor natural killer (CAR-NK) cell therapy represents a promising immunotherapeutic approach. CSPG4 (chondroitin sulfate proteoglycan 4), a tumor-associated antigen overexpressed in GBM and critically involved in tumor proliferation and metastasis, was investigated as a therapeutic target. This study aimed to evaluate the efficacy of CSPG4-targeted CAR-NK cells in GBM treatment.

Methods and results

We engineered a second-generation CAR construct incorporating the CSPG4-specific scFv 763.74, a CD8 transmembrane domain, and intracellular co-stimulatory/activation domains from CD28 and CD3ζ. The resulting CAR-NK cells were tested for anti-tumor activity in vitro and in vivo. Results demonstrated that CSPG4-directed CAR-NK cells selectively recognized and lysed CSPG4-positive GBM cells, significantly suppressing tumor growth in preclinical models compared to control NK cells. Mechanistic studies confirmed that cytotoxicity was mediated through specific CSPG4 antigen engagement.

Conclusion

CSPG4-targeted CAR-NK cells exhibit potent anti-GBM activity, highlighting their potential as a novel immunotherapy. These findings provide a robust preclinical foundation for advancing CSPG4-directed CAR-NK cell therapy into clinical trials, addressing the urgent need for effective treatments in GBM management.