虽然诱导铁死和抑制转化生长因子 β（TGF-β）信号通路是改造肿瘤微环境（TME）和使生成低免疫原性的肿瘤对免疫检查点抑制剂（ICI）疗法响应的有效方法，但剂量限制的副作用仍然是阻碍其临床应用的主要障碍。在此基础上，我们开发了一种新型的索拉非尼和抗TGF-β抗体负载的Fe3O4/Gd2O3杂化纳米粒子，其与RGD二聚体结合（FeGd-HN@索拉非尼@TGF-β抗体@RGD2，FG-STR）。索拉非尼显著增强FeGd-HN引发的铁死和诱导损伤相关分子图谱从铁死癌细胞释放以提高树突状细胞（DCs）的成熟和吞噬作用，而抗TGF-β抗体进一步与增强的铁死相互作用以促进DC成熟和CD8+ T细胞的招募，从而加热TME。此外，RGD2的融合有助于肿瘤细胞对FG-STR的吞噬作用，从而显著降低索拉非尼和抗TGF-β抗体的剂量以避免剂量限制性毒性。最后，体外和体内实验表明FG-STR具有显著优越的内在磁共振成像能力，比Gadovist更有效地抑制肿瘤生长和肺转移，并增强了抗程序性细胞死亡-1治疗的疗效。综上所述，本研究提供了一种有前途的新型磁共振成像引导TME加热治疗策略。

Although induction of ferroptosis and inhibition of transforming growth factor-β (TGF-β) signaling are both effective ways to reform the tumor microenvironment (TME) and render low-immunogenic tumors responsive to immune checkpoint inhibitor (ICI) therapy, dose-limiting side effects remain major obstacles hindering their clinical application. Herein, a novel sorafenib and anti-TGF-β antibody loaded Fe3 O4 /Gd2 O3 hybrid nanoparticles with conjugation of RGD dimer (FeGd-HN@Sorafenib@TGF-β-antibody@RGD2, FG-STR) is developed. Sorafenib significantly enhances FeGd-HN-triggered ferroptosis and improves maturation and phagocytosis of dendritic cells (DCs) by inducing damage-associated molecular patterns released from ferroptotic cancer cells, while the anti-TGF-β antibody further synergizes with enhanced ferroptosis to promote DC maturation and the recruitment of CD8+ T cells, thus heating the TME. Moreover, incorporation of RGD2 facilitates uptake of the FG-STR in tumor cells which led to a significant dosage reduction of both sorafenib and anti-TGF-β antibody to avoid dose-limiting toxicities. Finally, in vitro and in vivo experiments shows that FG-STR has significantly superior intrinsic magnetic resonance imaging (MRI) capability than that of Gadovist, effectively inhibits tumor growth and lung metastasis, and increased the efficacy of anti-programmed cell death-1 treatment. Taken together, this study provides a promising strategy for new advanced MRI-guided TME heating therapies. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.