CCL3 and IL‐7 Synergistically Enhance CAR‐T Efficacy in Solid Tumors

ABSTRACT Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable clinical efficacy, but challenges remain in the therapeutic application for solid tumors, primarily due to poor infiltration capacity, suboptimal activity, and tumor antigen escape. Here, we found that the chemokine CCL3 plays a significant role in modulating intratumoral T cell cytotoxicity. However, CCL3 alone is insufficient to sustain durable CAR‐T cell‐mediated tumor killing, largely due to tumor‐induced T cell death. In contrast, the combination of CCL3 with interleukin‐7 (IL‐7), a cytokine known to enhance T cell survival, exerted a potent synergistic effect. This combination significantly improved CAR‐T cell infiltration and longevity in solid tumors, leading to robust anti‐tumor efficacy without significant side effects or systemic toxicity. Mechanistically, CCL3 plus IL‐7 promoted RUNX3 expression and facilitated the differentiation of CD69 ⁺ CD103 ⁺ tissue‐resident memory T (Trm) cells. Furthermore, treatment with CAR‐T cells co‐expressing CCL3 and IL‐7 (3P7‐CAR‐T) remodeled the immune landscape of solid tumors, marked by an increased infiltration of M1‐like macrophages and CD103 ⁺ migratory dendritic cells. These changes enhance antigen presentation, thereby promoting the priming of endogenous anti‐tumor T cell responses. Taken together, our results demonstrate that CCL3 synergizes with IL‐7 to augment CAR‐T cell memory and therapeutic effectiveness in solid tumors.