Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang, China.
Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Hangzhou 310009, Zhejiang, China.
ACS Nano. 2024 Jun 18;18(24):15864-15877. doi: 10.1021/acsnano.4c02947. Epub 2024 Jun 3.
Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery , we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.
三阴性乳腺癌(TNBC)是一种高度侵袭性的恶性肿瘤,缺乏有效的靶向治疗方法。诱导肿瘤细胞发生免疫原性细胞死亡(ICD)代表了一种通过促进抗肿瘤免疫来提高治疗效果的有前途的策略。紫杉醇(PTX)是一种常用于 TNBC 的化疗药物,可诱导 ICD;然而,由此产生的免疫原性是有限的。因此,迫切需要探索通过结合免疫调节药物来提高 TNBC 中 ICD 有效性的策略。本研究探讨了塞来昔布(CXB)通过阻断肿瘤细胞中 PGE 的生物合成来增强 PTX 诱导的 ICD 的潜力。我们观察到 CXB 和 PTX 的联合作用促进了树突状细胞的成熟,并引发了 T 细胞依赖性免疫反应,导致在疫苗接种实验中增强了肿瘤排斥。为了进一步优化药物传递,我们开发了 cRGD 修饰的脂质体用于 CXB 和 PTX 的靶向共递药。该递药系统显著提高了药物积累,并在 TNBC 的原位小鼠模型中引发了强烈的抗肿瘤免疫。此外,它还作为原位疫苗抑制肿瘤复发和肺转移。总体而言,我们的研究结果深入了解了 CXB 和 PTX 联合治疗的治疗机制,强调了它们作为 TNBC 有效免疫治疗方法的潜力。