Enhancing CAR-T Cell Efficacy in Solid Tumors by Inhibiting CCL5/VEGF-Mediated Angiogenesis

  • Adv Sci (Weinh). 2026 May 6:e21975. doi: 10.1002/advs.202521975.
Shishuo Sun  1  2  3 ,  Qihong Li  1  2  3 ,  Bixi Wang  1  3 ,  Gang Wang  1  2 ,  Ying Xue  1  2 ,  Yibing Liang  1  2 ,  Chenhe Hu  1  2 ,  Zhenyu Wang  1  2 ,  Xiaoge Gao  1  2  3 ,  Haiheng Xu  1  2  3 ,  Jun Song  1  4 ,  Hailong Li  1  5 ,  Liantao Li  1  6 ,  Xiaoxiao Liu  1  6 ,  Patrick Ming-Kuen Tang  7 ,  Qing Zhang  1  2  3
Affiliations
  • 1. Cancer Institute, Cellular Therapeutics School of Medicine, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China.
  • 2. Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China.
  • 3. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China.
  • 4. Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China.
  • 5. Department of Urology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China.
  • 6. Department of Radiation Oncology, Cancer Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, P.R. China.
  • 7. Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Shatin, Hong Kong, P.R. China.
PMID: 42089445 DOI: 10.1002/advs.202521975
Abstract

Chimeric antigen receptor-modified T cells (CAR-T) have shown remarkable success in hematologic malignancies, but their efficacy against solid tumors remains limited. While immunosuppressive cells and molecules in the tumor microenvironment (TME) are known to impair CAR-T function, these are not CAR-T-specific barriers. Using multiple mouse models, we found that the impact of CAR-T cells on tumor growth is dose-dependent, capable of promoting, having no effect on, or inhibiting tumor growth. Mechanistically, tumor-infiltrating CAR-T cells play a dual role: they release antitumor effector molecules (e.g., IFN-γ, TNF-α), but also produce CCL5, which promotes tumor growth by inducing VEGF and angiogenesis. CCL5-mediated protumor activity was identified as a key limiting factor for CAR-T efficacy. Importantly, combining CCL5-knockout CAR-T cells with the CCR5 Inhibitor maraviroc significantly enhanced antitumor efficacy. These findings reveal a mechanism constraining CAR-T function in solid tumors and suggest promising combination strategies to improve therapeutic outcomes.

Keywords
CAR‐T; CCL5; VEGF; solid tumor; tumor angiogenesis.
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