肿瘤细胞治疗研究
英文原题：The JAK1 inhibitor golidocitinib boosts therapeutic potency of DLL3-targeted CAR-T therapy for small cell lung cancer.
小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，有效治疗选择有限。
小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，目前有效治疗选择有限。靶向DLL3的CAR-T疗法显示出良好的抗肿瘤潜力，但常受T细胞耗竭限制，影响其长期疗效。本研究发现，高选择性JAK1抑制剂golidocitinib可通过抑制STAT3磷酸化并调节凋亡相关基因，在体外诱导SCLC细胞凋亡。该药还降低抗DLL3 CAR-T细胞耗竭标志物的表达，促进记忆T细胞表型形成，并增强CAR-T细胞在体外和体内的持久性。与抗DLL3 CAR-T疗法联合使用时，golidocitinib在体外细胞毒性实验和体内模型中均显著增强抗肿瘤疗效，且未见明显器官毒性。综上，研究结果表明golidocitinib具有双重抗肿瘤作用，为SCLC治疗提供了一种新颖且有前景的策略。
Small cell lung cancer (SCLC) is an aggressive malignancy with limited effective therapeutic options. DLL3-targeted CAR-T therapy shows promising anti-tumor potential but is often restricted by T-cell exhaustion, which impairs its long-term efficacy. In the present study, we found that golidocitinib, a highly selective JAK1 inhibitor, induces apoptosis in SCLC cells in vitro via inhibiting STAT3 phosphorylation and regulating apoptosis associated genes. It also reduced the expression of exhaustion markers in anti-DLL3 CAR-T cells, promoted the formation of memory T cell phenotypes, and enhanced CAR-T cell persistence both in vitro and in vivo. When combined with anti-DLL3 CAR-T therapy, golidocitinib significantly augmented anti-tumor efficacy in both in vitro cytotoxicity assays and in vivo models, without obvious organ toxicity. These findings collectively demonstrate the dual anti-tumor effects of golidocitinib, thus providing a novel and promising strategy for SCLC treatment.
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