肿瘤治疗学中针对免疫系统的治疗方法已经改善了患者在广泛的肿瘤类型中的预后，但是由于抑制性肿瘤微环境（TME）中T细胞反应不足导致抵抗仍然是一个重要的问题。新型治疗方法可以激活先天免疫反应并缓解这种抑制，这有助于克服这个障碍。TAK-676是一种人工合成可注射的新型干扰素基因（STING）激动剂。我们在这里证明，TAK-676剂量依赖地触发了STING信号通路的激活和第一型干扰素的激活。此外，我们还表明，TAK-676是一种高度有效的先天免疫系统和适应性免疫系统调节剂，并促进了在临床前模型中树突状细胞、自然杀伤细胞和T细胞的激活。 在体内的同种异体小鼠肿瘤模型中，TAK-676剂量依赖地诱导了细胞因子反应，并增加了TME和肿瘤相关淋巴组织中免疫细胞的激活和增殖。此外，我们还证明，TAK-676的剂量给药结果表现出重要的STING依赖性抗肿瘤活性，包括完全消退和持久的记忆T细胞免疫力。我们显示出TAK-676耐受性好，在血浆中表现出剂量比例规律的药代动力学，并在肿瘤中表现出更高的暴露。TAK-676的静脉注射在广泛的肿瘤类型中提供了潜在的治疗益处。TAK-676的第一人类临床试验正在进行中。TAK-676是一种新型全身性STING激动剂，可引起先天免疫和适应性免疫活性的强烈激活，从而在多个同种异体肿瘤模型中产生持久的抗肿瘤反应。TAK-676的临床研究正在进行中。©2022作者；由美国癌症研究协会出版。

Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing.TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing.© 2022 The Authors; Published by the American Association for Cancer Research.