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

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.