使用光热疗法（PTT）和免疫疗法的联合疗法是引发宿主免疫反应以消融肿瘤的最有前途的方法之一。然而，由于免疫细胞浸润和细胞免疫反应效率低下，其治疗效果受到限制。在这项研究中，开发了一种具有同源靶向的仿生免疫刺激纳米调节剂Tm@PDA-GA（4T1膜@聚多巴胺-藤黄酸）。 4T1 膜 (Tm) 涂层降低了免疫原性并促进肿瘤细胞对 Tm@PDA-GA 的摄取。聚多巴胺（PDA）作为药物载体可以在近红外线（NIR）照射下诱导PTT和免疫原性细胞死亡（ICD）以激活树突状细胞（DC）。此外，Tm@PDA-GA在酸性肿瘤微环境中按需释放藤黄酸（GA），抑制热休克蛋白（HSP）的表达，实现协同化学光热抗肿瘤活性，并增加4T1细胞的ICD。更重要的是，GA可以通过抑制HIF-1α和VEGF使血管正常化，从而增强免疫浸润并缓解缺氧应激。因此，Tm@PDA-GA 诱导 ICD、激活 DC、刺激细胞毒性 T 细胞并抑制 Tregs。此外，Tm@PDA-GA与抗PD-L1结合可进一步增强肿瘤免疫反应，有效抑制肿瘤生长和肺转移。总之，生物材料介导的 PTT 与血管正常化相结合是三阴性乳腺癌 (TNBC) 有效免疫治疗的一种有前景的策略。© 2024 Wiley‐VCH GmbH。

Combination therapy using photothermal therapy (PTT) and immunotherapy is one of the most promising approaches for eliciting host immune responses to ablate tumors. However, its therapeutic efficacy is limited due to inefficient immune cell infiltration and cellular immune responses. In this study, a biomimetic immunostimulatory nanomodulator, Tm@PDA-GA (4T1 membrane@polydopamine-gambogic acid), with homologous targeting is developed. The 4T1 membrane (Tm) coating reduced immunogenicity and facilitated uptake of Tm@PDA-GA by tumor cells. Polydopamine (PDA) as a drug carrier can induce PTT under near-infrared ray (NIR) irradiation and immunogenic cell death (ICD) to activate dendritic cells (DCs). Moreover, Tm@PDA-GA on-demand released gambogic acid (GA) in an acidic tumor microenvironment, inhibiting the expression of heat shock proteins (HSPs) for synergetic chemo-photothermal anti-tumor activity and increasing the ICD of 4T1 cells. More importantly, GA can normalize the vessels via HIF-1α and VEGF inhibition to enhance immune infiltration and alleviate hypoxia stress. Thus, Tm@PDA-GA induced ICD, activated DCs, stimulated cytotoxic T cells, and suppressed Tregs. Moreover, Tm@PDA-GA is combined with anti-PD-L1 to further augment the tumor immune response and effectively suppress tumor growth and lung metastasis. In conclusion, biomaterial-mediated PTT combined with vessel normalization is a promising strategy for effective immunotherapy of triple-negative breast cancer (TNBC).© 2024 Wiley‐VCH GmbH.