Stable Cyclometalated Gold(III) Complex Engaging Isoquinoline Derivative and Disulfur Ligand Elicits Necroptosis-Dependent Immunogenic Cell Death

Cancer
chemoimmunotherapy based on metal complexes has attracted
wide interest for its ability to eliminate tumor cells while activating
antitumor immunity, primarily by inducing immunogenic cell death (ICD).
However, clinical translation of ICD inducers remains challenging,
underscoring the need for inducers that elicit ICD via alternative cell death mechanisms. Necroptosis represents a potent
yet underutilized route to trigger ICD. Herein, we designed a series
of stable Au(III) complexes incorporating an isoquinoline-derived
cyclometalated C^N ligand and various strong electron-donating S^S
or N^N auxiliary ligands. Among them, Au-1 exhibited
potent cytotoxicity, inhibited thioredoxin reductase (TrxR), elevated
intracellular ROS, and triggered ROS-mediated necroptosis. This process
elicited robust necroptosis-dependent ICD. In vivo, Au-1 significantly suppressed tumor growth, remodeled
the tumor immune microenvironment, and synergized effectively with
anti-PD-1 therapy. This work presents the first rationally designed
cyclometalated Au(III) complex that functions as a necroptosis-dependent
ICD inducer, offering a promising strategy for metal-based chemoimmunotherapy.

癌症领域中，基于金属配合物的化学免疫疗法因可在杀伤肿瘤细胞的同时激活抗肿瘤免疫，且主要通过诱导免疫原性细胞死亡（immunogenic cell death, ICD）发挥作用，已受到广泛关注。然而，免疫原性细胞死亡诱导剂的临床转化仍面临诸多挑战，这凸显了开发可通过替代细胞死亡途径诱发ICD的诱导剂的迫切需求。坏死性凋亡（necroptosis）便是一种强效但尚未得到充分利用的触发ICD的途径。
在此研究中，我们设计了一系列稳定的Au(III)配合物，这类配合物搭载了异喹啉衍生的环金属化C^N配体以及多种强给电子型S^S或N^N辅助配体。其中，Au-1展现出强效细胞毒性，可抑制硫氧还蛋白还原酶（thioredoxin reductase, TrxR）、升高细胞内活性氧（reactive oxygen species, ROS）水平，并诱发ROS介导的坏死性凋亡。该过程可触发显著依赖于坏死性凋亡的ICD。
在体内实验中，Au-1可显著抑制肿瘤生长，重塑肿瘤免疫微环境，并与抗PD-1治疗产生良好的协同效应。本研究首次报道了经理性设计的环金属化Au(III)配合物，其可作为依赖坏死性凋亡的ICD诱导剂，为基于金属的化学免疫疗法提供了极具前景的策略。