Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, PR China.
J Control Release. 2023 Mar;355:211-227. doi: 10.1016/j.jconrel.2023.01.075. Epub 2023 Feb 7.
Although cancer immunotherapy has achieved remarkable progress, the clinical treatment of triple-negative breast cancer (TNBC) is still tough to make a breakthrough. The unsatisfactory therapeutic effect may be attributed to the lack of tumor immunogenicity and the strong immunosuppressive tumor microenvironment (ITM). In order to overcome the above shortcomings, engineering nanoparticles (P-aCD24/CEL + P/shMFN1) was designed to deliver anti-CD24 monoclonal antibody (aCD24), celastrol (CEL) and mitofusin 1 shRNA (shMFN1) for synergistic tumor cells-targeted treatment and tumor-associated macrophages (TAMs)-targeted immunomodulation. CD24, highly expressed on tumor cells, interacts with Siglec10 on TAMs to protect tumor cells from phagocytosis by macrophages, and thus has become a novel and dominant immune checkpoint in TNBC. P-aCD24/CEL achieved the release of aCD24 based on the dual response of carrier to pH and MMP2 in tumor microenvironment. Moreover, CEL increased "eat me" signal CRT and induced the immunogenic cell death (ICD) of tumor cells, together with decreased "don't eat me" signal CD24, reactivated macrophage phagocytosis of tumor cells, and ultimately improves the macrophage-based immunotherapy. On the other hand, P/shMFN1 could target TAMs for mitochondrial dynamics regulation via durable MFN1 silencing in TAMs, thereby reversing the phenotype of M2-TAMs. P-aCD24/CEL and P/shMFN1 could synergistically elicit evident antitumor immune responses and long-term immune memory to significantly inhibit tumor progress and postoperative recurrence. Based on remodeling the ITM and increasing antitumor immune response, this combination immunotherapy strategy showed great potential for TNBC treatment.
尽管癌症免疫疗法已经取得了显著的进展，但三阴性乳腺癌（TNBC）的临床治疗仍然难以取得突破。治疗效果不理想的原因可能是肿瘤缺乏免疫原性和强大的免疫抑制肿瘤微环境（ITM）。为了克服上述缺点，设计了工程纳米颗粒（P-aCD24/CEL+P/shMFN1）来递送抗 CD24 单克隆抗体（aCD24）、雷公藤红素（CEL）和线粒体融合蛋白 1 shRNA（shMFN1），以协同靶向肿瘤细胞和肿瘤相关巨噬细胞（TAMs）的免疫调节。CD24 在肿瘤细胞上高度表达，与 TAMs 上的 Siglec10 相互作用，保护肿瘤细胞免受巨噬细胞的吞噬，因此已成为 TNBC 中的一种新型且主要的免疫检查点。P-aCD24/CEL 基于载体对肿瘤微环境中 pH 和 MMP2 的双重响应实现了 aCD24 的释放。此外，CEL 增加了“吃我”信号 CRT 并诱导肿瘤细胞的免疫原性细胞死亡（ICD），同时降低了“不要吃我”信号 CD24，重新激活了巨噬细胞对肿瘤细胞的吞噬作用，最终改善了基于巨噬细胞的免疫治疗。另一方面，P/shMFN1 可以通过在 TAMs 中持久沉默 MFN1 来靶向 TAMs 以调节线粒体动力学，从而逆转 M2-TAMs 的表型。P-aCD24/CEL 和 P/shMFN1 可以协同引发明显的抗肿瘤免疫反应和长期免疫记忆，从而显著抑制肿瘤进展和术后复发。基于重塑 ITM 和增强抗肿瘤免疫反应，这种联合免疫治疗策略显示出治疗 TNBC 的巨大潜力。
