材料科学
免疫系统
细胞外基质
免疫原性细胞死亡
肿瘤微环境
纳米技术
程序性细胞死亡
药物输送
细胞凋亡
间质细胞
癌症研究
化学
细胞生物学
生物
免疫学
生物化学
医学
作者
Yuxin Zhang,Zaixiang Fang,Dayi Pan,Yunkun Li,Jie Zhou,Hongying Chen,Zhiqian Li,Mengli Zhu,Jia Li,Qin Lijuan,Xiangyi Ren,Qiyong Gong,Kui Luo
标识
DOI:10.1002/adma.202401304
摘要
The dense extracellular matrix (ECM) in solid tumors, contributed by cancer-associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. A sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) is proposed to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. Dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)-based nanomedicines (poly[OEGMA-Dendron(G2)-Gly-Phe-Leu-Gly-DAS] (P-DAS) and poly[OEGMA-Dendron(G2)-hydrazone-Epi] (P-Epi)) are developed for sequential delivery of DAS and Epi, respectively. P-DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM can enhance tumor penetration of P-Epi to strengthen its ICD effect, leading to an amplified antitumor immune response. In breast cancer-bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti-programmed cell death 1 (PD-1) therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P-DAS and P-Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier.
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