DataVXAdvanced SciencePaper
journal article·2026-07Open access

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

Shishuo Sun, Qihong Li, Bixi Wang, Gang Wang, Ying Xue, Yibing Liang, Chenhe Hu, Zhenyu Wang, Xiaoge Gao, Haiheng Xu, Jun Song, Hailong Li, Liantao Li, Xiaoxiao Liu, Patrick Ming‐Kuen Tang, Qing Zhang

Advanced Science· Volume 13· Issue 42
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Source abstract

Abstract

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.
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Research context

OpenAlex topics: CAR-T cell therapy research · Immunotherapy and Immune Responses · Immune Cell Function and Interaction

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Cancer Institute Cellular Therapeutics School of Medicine Xuzhou Medical University Xuzhou Jiangsu P.R. China

Center of Clinical Oncology The Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu P.R. China

Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy Xuzhou Medical University Xuzhou Jiangsu P.R. China

Department of General Surgery The Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu China

Department of Urology The Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu P.R. China

Department of Radiation Oncology Cancer Center The Affiliated Hospital of Xuzhou Medical University Xuzhou Jiangsu P.R. China

Department of Anatomical and Cellular Pathology State Key Laboratory of Translational Oncology The Chinese University of Hong Kong Shatin Hong Kong P.R. China

Funding

National Natural Science Foundation of China

References (41)

Show source-provided references
1. 10.3389/fimmu.2022.92715310.3389/fimmu.2022.927153 ↗
2. 10.1016/j.canlet.2024.21687110.1016/j.canlet.2024.216871 ↗
3. 10.1038/s41571‐023‐00754‐110.1038/s41571‐023‐00754‐1 ↗
4. 10.1182/blood‐2011‐05‐35444910.1182/blood‐2011‐05‐354449 ↗
5. 10.1038/nm.188210.1038/nm.1882 ↗
6. 10.1056/NEJMoa161049710.1056/NEJMoa1610497 ↗
7. 10.1186/s13045‐021‐01128‐910.1186/s13045‐021‐01128‐9 ↗
8. 10.1038/s41417‐019‐0104‐z10.1038/s41417‐019‐0104‐z ↗
9. 10.1136/jitc‐2020‐00109710.1136/jitc‐2020‐001097 ↗
10. 10.1038/s41591‐022‐01800‐810.1038/s41591‐022‐01800‐8 ↗
11. 10.1016/j.ccell.2025.03.01910.1016/j.ccell.2025.03.019 ↗
12. 10.1016/j.immuni.2023.09.01010.1016/j.immuni.2023.09.010 ↗
13. 10.2174/15665231380480657010.2174/156652313804806570 ↗
14. 10.1080/14737140.2017.139528510.1080/14737140.2017.1395285 ↗
15. 10.1038/s41586‐023‐06243‐w10.1038/s41586‐023‐06243‐w ↗
16. 10.1186/s12967‐023‐04292‐310.1186/s12967‐023‐04292‐3 ↗
17. 10.1158/2326‐6066.CIR‐22‐053110.1158/2326‐6066.CIR‐22‐0531 ↗
18. 10.1186/s12964‐025‐02648‐410.1186/s12964‐025‐02648‐4 ↗
19. 10.1016/j.immuni.2020.07.02310.1016/j.immuni.2020.07.023 ↗
20. 10.1016/j.ccell.2019.01.00210.1016/j.ccell.2019.01.002 ↗
21. 10.1016/j.ccell.2019.05.00410.1016/j.ccell.2019.05.004 ↗
22. 10.1158/2159‐8290.CD‐19‐007410.1158/2159‐8290.CD‐19‐0074 ↗
23. 10.1038/s41467‐020‐15375‐w10.1038/s41467‐020‐15375‐w ↗
24. 10.1172/jci.insight.13726310.1172/jci.insight.137263 ↗
25. 10.1158/0008‐5472.CAN‐08‐432910.1158/0008‐5472.CAN‐08‐4329 ↗
26. 10.3390/cancers1207176510.3390/cancers12071765 ↗
27. 10.1016/j.coi.2024.10251010.1016/j.coi.2024.102510 ↗
28. 10.18632/oncotarget.253210.18632/oncotarget.2532 ↗
29. 10.1111/jcmm.1848910.1111/jcmm.18489 ↗
30. 10.1002/cam4.294110.1002/cam4.2941 ↗
31. 10.1016/j.phrs.2021.10603610.1016/j.phrs.2021.106036 ↗
32. 10.1158/1541‐7786.MCR‐22‐087210.1158/1541‐7786.MCR‐22‐0872 ↗
33. 10.1080/2162402X.2021.201090510.1080/2162402X.2021.2010905 ↗
34. 10.1158/0008‐5472.CAN‐10‐015310.1158/0008‐5472.CAN‐10‐0153 ↗
35. 10.1007/s00262‐022‐03193‐610.1007/s00262‐022‐03193‐6 ↗
36. 10.1038/s41423‐021‐00655‐210.1038/s41423‐021‐00655‐2 ↗
37. 10.1001/jamaoncol.2016.441910.1001/jamaoncol.2016.4419 ↗
38. 10.1007/s11756‐023‐01326‐510.1007/s11756‐023‐01326‐5 ↗
39. 10.1016/j.canlet.2023.21651110.1016/j.canlet.2023.216511 ↗
40. 10.1038/s41467‐023‐38426‐410.1038/s41467‐023‐38426‐4 ↗
41. 10.1073/pnas.230374012010.1073/pnas.2303740120 ↗