Tertiary lymphoid structures (TLSs) in tumor tissues facilitate immune cell trafficking and cytotoxicity, which benefits survival and favorable responses in immune therapy. Here, we observed a high correlation of tumor necrosis factor superfamily member 14 (LIGHT) expression with TLS signature genes, which are all markers for immune cell accumulation and better prognosis, through retrieving RNA sequencing (RNA-seq) data from patients with cancer, suggesting the potential of LIGHT in reconstituting a high immune-infiltrated tumor microenvironment. Accordingly, LIGHT co-expressed chimeric antigen receptor T (LIGHT CAR-T) cells not only showed enhanced cytotoxicity and cytokine production but also improved CCL19 and CCL21 expression by surrounding cells. And the supernatant of LIGHT CAR-T cells promoted T cell migration in a paracrine manner. Furthermore, LIGHT CAR-T cells showed superior anti-tumor efficacy and improved infiltration in comparison with conventional CAR-T cells in immunodeficient NSG mice. Accordingly, murine LIGHT-OT-1 T cells normalized tumor blood vessels and enforced intratumoral lymphoid structures in C57BL/6 syngeneic tumor mouse models, implying the potential of LIGHT CAR-T in clinical application. Taken together, our data revealed a straightforward strategy to optimize trafficking and cytotoxicity of CAR-T cells by redirecting TLSs through LIGHT expression, which has great potential to expand and optimize the application of CAR-T therapy in solid tumors.

肿瘤组织中的三级淋巴结构（TLS）促进免疫细胞运输和细胞毒性，这有利于免疫治疗的生存和良好反应。在这里，我们通过检索癌症患者的 RNA 测序 (RNA-seq) 数据，观察到肿瘤坏死因子超家族成员 14 (LIGHT) 表达与 TLS 特征基因的高度相关性，这些基因都是免疫细胞积累和更好预后的标志物，这表明光在重建高度免疫浸润的肿瘤微环境方面具有潜力。因此，LIGHT共表达嵌合抗原受体T（LIGHT CAR-T）细胞不仅表现出增强的细胞毒性和细胞因子产生，而且还改善了周围细胞的CCL19和CCL21表达。 LIGHT CAR-T细胞上清液以旁分泌方式促进T细胞迁移。此外，与传统 CAR-T 细胞相比，LIGHT CAR-T 细胞在免疫缺陷 NSG 小鼠中表现出卓越的抗肿瘤功效并改善了浸润。因此，小鼠 LIGHT-OT-1 T 细胞在 C57BL/6 同基因肿瘤小鼠模型中使肿瘤血管正常化并增强瘤内淋巴结构，这意味着 LIGHT CAR-T 在临床应用中的潜力。总而言之，我们的数据揭示了一种通过 LIGHT 表达重定向 TLS 来优化 CAR-T 细胞运输和细胞毒性的简单策略，这对于扩大和优化 CAR-T 疗法在实体瘤中的应用具有巨大潜力。