光热疗法（PTT）是一种有前途的非侵入性治疗方法，在消除肿瘤方面显示出巨大的潜力。它不仅诱导癌细胞凋亡，还引发免疫原性细胞死亡（ICD），从而激活免疫系统对抗癌症。然而，免疫抑制的肿瘤微环境（TIME）对单次治疗引发强烈的免疫反应提出了挑战，从而限制了癌症免疫疗法的治疗效果。在这项研究中，双靶向纳米递送系统（GOx@FeNPs）与αPD-L1免疫检查点阻断剂相结合，可以通过介导PTT、铁死亡和抗肿瘤免疫反应来抑制结直肠癌（CRC）进展。简而言之，GOx@FeNPs 中的环精氨酸甘氨酰天冬氨酸 (cRGD) 肽和茴香酰胺 (AA) 实现了特异性肿瘤递送，不仅具有良好的光热效应实现 PTT 和诱导 ICD，而且还可以消耗谷胱甘肽 (GSH) 和催化内源性 H2O2 产生活性氧 (ROS)。所有这些都加速了Fenton反应并增强了PTT诱导的ICD过程。因此，大量的肿瘤特异性抗原被释放，刺激淋巴结中的树突状细胞（DC）成熟，增强CD8 T细胞在肿瘤中的浸润。同时与αPD-L1联合对CRC具有良好的协同作用，抑瘤率超过90%。此外，由于Fe3的存在，GOx@FeNPs在T2加权下具有良好的磁共振成像（MRI）能力，这有利于CRC的综合诊断和治疗系统。通过构建双靶点GOx@FeNPs纳米平台，实现PTT与铁死亡协同结合，提高免疫治疗效果，为CRC免疫治疗提供新途径。© 2024。作者。

Photothermal therapy (PTT) is a promising non-invasive treatment that has shown great potential in eliminating tumors. It not only induces apoptosis of cancer cells but also triggers immunogenic cell death (ICD) which could activate the immune system against cancer. However, the immunosuppressive tumor microenvironment (TIME) poses a challenge to triggering strong immune responses with a single treatment, thus limiting the therapeutic effect of cancer immunotherapy. In this study, dual-targeted nano delivery system (GOx@FeNPs) combined with αPD-L1 immune checkpoint blocker could inhibit colorectal cancer (CRC) progression by mediating PTT, ferroptosis and anti-tumor immune response. Briefly, specific tumor delivery was achieved by the cyclic arginine glycyl aspartate (cRGD) peptide and anisamide (AA)  in GOx@FeNPs which not only had a good photothermal effect to realize PTT and induce ICD, but also could deplete glutathione (GSH) and catalyze the production of reactive oxygen species (ROS) from endogenous H2O2. All these accelerated the Fenton reaction and augmented the process of PTT-induced ICD. Thus, a large amount of tumor specific antigen was released to stimulate the maturation of dendritic cells (DCs) in lymph nodes and enhance the infiltration of CD8+ T cells in tumor. At the same time, the combination with αPD-L1 has favorable synergistic effectiveness against CRC with tumor inhibition rate over 90%. Furthermore, GOx@FeNPs had good magnetic resonance imaging (MRI) capability under T2-weighting owing to the presence of Fe3+, which is favorable for integrated diagnosis and treatment systems of CRC. By constructing a dual-targeted GOx@FeNPs nanoplatform, PTT synergistically combined with ferroptosis was realized to improve the immunotherapeutic effect, providing a new approach for CRC immunotherapy.© 2024. The Author(s).