Antigen-specific T cell receptor-engineered T cell (TCR-T) based immunotherapy has proven to be an effective method to combat cancer. In recent years, cross-talk between the innate and adaptive immune systems may be requisite to optimize sustained antigen-specific immunity, and the stimulator of interferon genes (STING) is a promising therapeutic target for cancer immunotherapy. The level of expression or presentation of antigen in tumor cells affects the recognition and killing of tumor cells by TCR-T. This study aimed at investigating the potential of innate immune stimulation of T cells and engineered T cells to enhance immunotherapy for low-expression antigen cancer cells. We systematically investigated the function and mechanism of cross-talk between STING agonist diABZI and adaptive immune systems. We established NY-ESO-1 full knockout Mel526 cells for this research and found that diABZI activated STING media and TCR signaling pathways. In addition, the results of flow cytometry showed that antigens presentation from cancer cells induced by STING agonist diABZI also improved the affinity of TCR-T cells function against tumor cells in vitro and in vivo. Our findings revealed that diABZI enhanced the immunotherapy efficacy of TCR-T by activating STING media and TCR signaling pathways, improving interferon-γ expression, and increasing antigens presentation of tumor cells. This indicates that STING agonist could be used as a strategy to promote TCR-T cancer immunotherapy.

基于抗原特异性 T 细胞受体工程化 T 细胞 (TCR-T) 的免疫疗法已被证明是对抗癌症的有效方法。近年来，先天免疫系统和适应性免疫系统之间的串扰可能是优化持续抗原特异性免疫所必需的，而干扰素基因刺激物（STING）是癌症免疫治疗的一个有前景的治疗靶点。肿瘤细胞中抗原的表达或呈递水平影响TCR-T对肿瘤细胞的识别和杀伤。本研究旨在研究 T 细胞的先天免疫刺激和工程化 T 细胞增强低表达抗原癌细胞免疫治疗的潜力。我们系统地研究了STING激动剂diABZI与适应性免疫系统之间串扰的功能和机制。我们为此研究建立了 NY-ESO-1 全敲除 Mel526 细胞，发现 diABZI 激活了 STING 介质和 TCR 信号通路。此外，流式细胞术结果表明，STING激动剂diABZI诱导的癌细胞抗原呈递也提高了体外和体内TCR-T细胞功能对肿瘤细胞的亲和力。我们的研究结果表明，diABZI 通过激活 STING 介质和 TCR 信号通路、改善干扰素-γ 表达并增加肿瘤细胞的抗原呈递来增强 TCR-T 的免疫治疗效果。这表明STING激动剂可以作为促进TCR-T癌症免疫治疗的策略。