Regulatory T cells (Tregs) prevent autoimmunity and contribute to cancer progression. They exert contact-dependent inhibition of immune cells through the production of active transforming growth factor-β1 (TGF-β1). However, the absence of a specific surface marker makes inhibiting the production of active TGF-β1 to specifically deplete human Tregs but not other cell types a challenge. TGF-β1 in an inactive form binds to Tregs membrane protein Glycoprotein A Repetitions Predominant (GARP) and then activates it via an unknown mechanism. Here, we demonstrated that tumour necrosis factor receptor-associated factor 3 interacting protein 3 (TRAF3IP3) in the Treg lysosome is involved in this activation mechanism. Using a novel naphthalenelactam-platinum-based anticancer drug (NPt), we developed a new synergistic effect by suppressing ATP-binding cassette subfamily B member 9 (ABCB9) and TRAF3IP3-mediated divergent lysosomal metabolic programs in tumors and human Tregs to block the production of active GARP/TGF-β1 for remodeling the tumor microenvironment. Mechanistically, NPt is stored in Treg lysosome to inhibit TRAF3IP3-meditated GARP/TGF-β1 complex activation to specifically deplete Tregs. In addition, by promoting the expression of ABCB9 in lysosome membrane, NPt inhibits SARA/p-SMAD2/3 through CHRD-induced TGF-β1 signaling pathway. In addition to expose a previously undefined divergent lysosomal metabolic program-meditated GARP/TGF-β1 complex blockade by exploring the inherent metabolic plasticity, NPt may serve as a therapeutic tool to boost unrecognized Treg-based immune responses to infection or cancer via a mechanism distinct from traditional platinum drugs and currently available immune-modulatory antibodies.

调节性 T 细胞 (Treg) 可以预防自身免疫并促进癌症进展。它们通过产生活性转化生长因子-β1 (TGF-β1) 对免疫细胞产生接触依赖性抑制。然而，缺乏特定的表面标记物使得抑制活性 TGF-β1 的产生以特异性地消耗人类 Tregs 而不是其他细胞类型成为一项挑战。非活性形式的 TGF-β1 与 Tregs 膜蛋白糖蛋白 A 重复为主 (GARP) 结合，然后通过未知机制将其激活。在这里，我们证明 Treg 溶酶体中的肿瘤坏死因子受体相关因子 3 相互作用蛋白 3 (TRAF3IP3) 参与了这种激活机制。使用新型萘内酰胺-铂类抗癌药物 (NPt)，我们通过抑制肿瘤和人类 Tregs 中 ATP 结合盒亚家族 B 成员 9 (ABCB9) 和 TRAF3IP3 介导的不同溶酶体代谢程序来阻止产生新的协同效应活性 GARP/TGF-β1 重塑肿瘤微环境。从机制上讲，NPt 储存在 Treg 溶酶体中，抑制 TRAF3IP3 介导的 GARP/TGF-β1 复合物激活，从而特异性消耗 Tregs。此外，NPt通过促进溶酶体膜中ABCB9的表达，通过CHRD诱导的TGF-β1信号通路抑制SARA/p-SMAD2/3。除了通过探索固有的代谢可塑性来揭示先前未定义的不同溶酶体代谢程序介导的 GARP/TGF-β1 复合物阻断之外，NPt 还可以作为一种治疗工具，通过一种独特的机制来增强针对感染或癌症的未识别的基于 Treg 的免疫反应。来自传统的铂类药物和目前可用的免疫调节抗体。