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.

中文翻译：

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基于树枝状聚合物的纳米药物重塑肿瘤基质：提高药物渗透性并增强抗肿瘤免疫反应

实体瘤中由癌症相关成纤维细胞 (CAF) 形成的致密细胞外基质 (ECM) 会阻碍药物的渗透并降低其治疗效果。提出了通过CAF修饰剂（达沙替尼，DAS）重塑ECM的序贯治疗策略，以促进免疫原性细胞死亡（ICD）诱导剂（表阿霉素，Epi）通过凋亡囊泡的渗透，最终增强乳腺癌的治疗效果。树枝状聚（低聚（乙二醇）甲醚甲基丙烯酸酯）（POEGMA）为基础的纳米药物（聚[OEGMA-Dendron（G2）-Gly-Phe-Leu-Gly-DAS]（P-DAS）和聚[OEGMA-Dendron（ G2)-腙-Epi](P-Epi))被开发用于分别顺序递送DAS和Epi。 P-DAS 重新编程 CAF，通过下调胶原蛋白合成代谢和能量代谢来减少胶原蛋白，从而减少 ECM 沉积。受调节的ECM可以增强P-Epi的肿瘤渗透，从而增强其ICD效应，从而增强抗肿瘤免疫反应。在乳腺癌小鼠中，这种方法减轻了 ECM 屏障，从而减少了肿瘤负荷并增加了细胞毒性 T 淋巴细胞浸润，更令人鼓舞的是，它与抗程序性细胞死亡 1 (PD-1) 疗法有效协同，显着抑制肿瘤生长并预防肺转移。此外，用 P-DAS 和 P-Epi 连续治疗后几乎检测不到全身毒性。这种方法通过代谢靶向 CAF 来克服 ECM 屏障，为治疗促纤维增生性肿瘤开辟了一条新途径。