Ma Yichao, Lai Peng, Sha Zhou, Li Bing, Wu Jiangpeng, Zhou Xiaojun, He Chuanglong, Ma Xiaojun
Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China.
Shanghai YangZhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, 200092, China.
Bioact Mater. 2025 Jan 14;47:83-99. doi: 10.1016/j.bioactmat.2025.01.006. eCollection 2025 May.
The oncogene MYC is one of the most commonly activated oncogenic proteins in human tumors, with nearly one-fourth of osteosarcoma showing MYC amplification and exhibiting the worst clinical outcomes. The clinical efficacy of single radiotherapy, chemotherapy, and immunotherapy for such osteosarcoma is poor, and the dysregulation of MYC amplification and immune-suppressive tumor microenvironment (TME) may be potential causes of anti-tumor failure. To address the above issues, we developed an injectable TME-responsive nanocomposite hydrogel to simultaneously deliver an effective MYC inhibitor (NHWD-870) and IL11Rα-targeted liposomes containing cisplatin-loaded MnO (Cis/Mn@Lipo-IL11). After administration, NHWD-870 effectively degrades MYC and downregulates CCL2 and IL13 cytokines to trigger M1 type activation of macrophages. Meanwhile, targeted delivery of Cis/Mn@Lipo-IL11 reacts with excess intratumoral GSH to generate Mn and thus inducing excess active oxygen species (ROS) production through Fenton-like reaction, along with cisplatin, thereby inducing immunogenic cell death (ICD) to promote dendritic cell maturation. Through synergistic regulation of MYC and ICD levels, the immune microenvironment was reshaped to enhance immune infiltration. In the osteosarcoma-bearing model, the nanocomposite hydrogel significantly enhanced tumor T cell infiltration, induced effective anti-tumor immunity and attenuated lung metastasis. Therefore, our results reveal a powerful strategy for targeted combination therapy of MYC-amplified osteosarcoma.
癌基因MYC是人类肿瘤中最常见被激活的致癌蛋白之一，近四分之一的骨肉瘤显示出MYC扩增并表现出最差的临床结果。单一放疗、化疗和免疫疗法对这类骨肉瘤的临床疗效不佳，而MYC扩增失调和免疫抑制性肿瘤微环境（TME）可能是抗肿瘤失败的潜在原因。为了解决上述问题，我们开发了一种可注射的TME响应性纳米复合水凝胶，以同时递送有效的MYC抑制剂（NHWD-870）和含有负载顺铂的MnO的IL11Rα靶向脂质体（Cis/Mn@Lipo-IL11）。给药后，NHWD-870有效降解MYC并下调CCL2和IL13细胞因子，以触发巨噬细胞的M1型激活。同时，Cis/Mn@Lipo-IL11的靶向递送与肿瘤内过量的谷胱甘肽（GSH）反应生成Mn，从而通过类芬顿反应诱导过量活性氧（ROS）产生，同时还有顺铂，从而诱导免疫原性细胞死亡（ICD）以促进树突状细胞成熟。通过对MYC和ICD水平的协同调节，重塑免疫微环境以增强免疫浸润。在荷骨肉瘤模型中，纳米复合水凝胶显著增强肿瘤T细胞浸润，诱导有效的抗肿瘤免疫并减轻肺转移。因此，我们的结果揭示了一种针对MYC扩增骨肉瘤的靶向联合治疗的有力策略。
