肿瘤组织中基质阻碍药物渗透效率低下，导致药物治疗效果下降和免疫细胞浸润水平降低。在此，我们构建了一种聚乙二醇化的树突状表阿霉素（Epi）前药（Epi-P4D）来调节癌症相关成纤维细胞（CAF）的代谢，从而增强Epi渗透到小鼠结肠癌的多细胞肿瘤球体（MTS）和肿瘤组织中。 CT26）、小鼠乳腺癌（4T1）和人类乳腺癌（MDA-MB-231）模型。 Epi-P4D 对 CT26 MTS 的增强细胞毒性和显着的抗肿瘤功效归因于纤连蛋白、α-SMA 和胶原蛋白分泌的减少。此外，肿瘤组织基质的变薄和肿瘤细胞的有效根除促进了树突状细胞（DC）成熟和随后的免疫激活的免疫原性细胞死亡效应，包括增加CD4 T细胞群，减少CD4和CD8 T细胞过度激活和耗竭，放大自然杀伤（NK）细胞比例并有效激活它们。因此，这种树突状纳米药物可以使肿瘤组织的基质变薄，从而增强药物渗透并促进免疫细胞浸润，从而提高抗肿瘤功效。© 2024 作者。

Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells. Herein, we constructed a PEGylated dendritic epirubicin (Epi) prodrug (Epi-P4D) to regulate the metabolism of cancer-associated fibroblasts (CAFs), thus enhancing Epi penetration into both multicellular tumor spheroids (MTSs) and tumor tissues in mouse colon cancer (CT26), mouse breast cancer (4T1) and human breast cancer (MDA-MB-231) models. Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin, α-SMA, and collagen secretion. Besides, thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell (DC) maturation and subsequent immune activation, including elevating the CD4+ T cell population, reducing CD4+ and CD8+ T cell hyperactivation and exhaustion, and amplifying the natural killer (NK) cell proportion and effectively activating them. As a result, this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.© 2024 The Authors.