Abstract：
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.
摘要：
实体瘤中致密的细胞外基质（ECM），由癌症相关成纤维细胞（CAF）贡献，阻碍药物渗透并降低其治疗效果。通过CAF修饰剂（达沙替尼，DAS）被提议促进免疫原性细胞死亡（ICD）诱导剂（表柔比星，Epi)通过凋亡囊泡，最终增强对乳腺癌的治疗效果。树枝状聚（低聚（乙二醇）甲基醚甲基丙烯酸酯）（POEGMA）基纳米药物（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DAS和Epi，分别。P-DAS重新编程CAFs通过下调胶原合成代谢和能量代谢来减少胶原，从而减少ECM沉积。调节的ECM可以增强P-Epi的肿瘤渗透以增强其ICD作用，导致放大的抗肿瘤免疫反应。在患有乳腺癌的小鼠中，这种方法减轻了ECM障碍，导致肿瘤负荷减少和细胞毒性T淋巴细胞浸润增加，更令人鼓舞的是，与抗程序性细胞死亡1（PD-1）治疗有效协同作用，显著抑制肿瘤生长和防止肺转移。此外，P-DAS和P-Epi序贯治疗后,全身毒性几乎无法检测到.这种方法为通过代谢靶向CAF以克服ECM屏障来治疗促结缔组织增生性肿瘤开辟了新途径。
