以嵌合性抗原受体T细胞为代表的新兴免疫细胞技术在治疗急性白血病为主的血液型恶性肿瘤中取得了瞩目的成就。然而，在治疗实体肿瘤的过程中，当前的CAR-T细胞免疫疗法相较于传统治疗手段，并无显著改善，研发靶向清除实体肿瘤的CAR-T细胞疗法迫在眉睫。.实体肿瘤中浸润免疫细胞表面的PD-1，Tim-3，Lag-3的高表达通常会导致CAR-T细胞的快速耗竭，我们前期通过研究发现，敲减CAR-T细胞表面PD-1，Tim-3，Lag-3等抑制性受体可以通过上调CD56表达而显著提升CAR-T细胞清除肿瘤的能力。然而，敲减三个抑制性受体或者过表达CD56的慢病毒滴度较低，制备成本较高。为此，我们从成药库中筛选获取可提升CAR-T细胞CD56表达的药物5-HT，并通过肿瘤类器官、肿瘤类器官荷瘤动物模型进一步评估该药物诱导CD56表达的Her2-CAR-T细胞浸润、分泌炎性细胞因子、杀伤肿瘤/类器官的能力。

Adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells has shown striking efficacy for the treatment of some human tumors especially the CD19-positive hematologic malignant tumors. However, CAR-T cell therapy seems to be inefficient when targeting solid tumors owing to upregulated co-inhibitory ligands that bind to inhibitory receptors on T cells. It is quite urgent to develop and optimize novel CAR-T cells therapy to overcome the tumor inhibitory microenvironment and achieve sufficient functional T cell infiltration.. The inhibitory receptors PD-1, Tim-3, and Lag-3 are highly expressed on tumor-infiltrating lymphocytes and compromise their antitumor activity.Here we downregulate these three checkpoint receptors simultaneously on CAR-T cells and that show the resulting PTL-CAR-T cells undergo epigenetic modifications and better control tumor growth. Mechanistically, PTL-CART cells enhanced their effector function through upregulating CD56 (NCAM). However, Lentivirus that genetic blockade of three checkpoint inhibitory receptors or highly expression of CD56 on CAR-T cells always exhibit very low titers. To augment the potency of engineered T cells, we screened 5-HT highly induced the expression of CD56. To test the screened drug (5HT) ,patient-derived organoids and patient-derived organoids xenografts will be introduced to evluate the infiltration, cytokine-secretion and cytotoxicity potencies of 5-HT treated Her2-CAR-T cells.