Glioblastoma is the most common and aggressive form of primary brain cancer, with median survival of 16–20 months and a 5‐year survival rates of <5%. Recent advances in immunotherapies have shown that addressing the tumor immune profile by targeting the colony‐stimulating factor 1 (CSF‐1) signaling pathway of tumor‐associated macrophages (TAMs) has the potential to improve glioblastoma therapy. However, such therapies have shown limited successes in clinical translation partially due to lack of specific cell targeting in solid tumors and systemic toxicity. In this study, we present a novel hydroxyl dendrimer‐mediated immunotherapy to deliver CSF‐1R inhibitor BLZ945 (D‐BLZ) from systemic administration selectively to TAMs in glioblastoma brain tumors to repolarize the tumor immune environment in a localized manner. We show that conjugation of BLZ945 to dendrimers enables sustained release in intracellular and intratumor conditions. We demonstrate that a single systemic dose of D‐BLZ targeted to TAMs decreases pro‐tumor expression in TAMs and promotes cytotoxic T cell infiltration, resulting in prolonged survival and ameliorated disease burden compared to free BLZ945. Our results demonstrate that dendrimer‐drug conjugates can facilitate specific, localized manipulation of tumor immune responses from systemic administration by delivering immunotherapies selectively to TAMs, thereby improving therapeutic efficacy while reducing off‐target effects.

中文翻译：

---

CSF-1R抑制剂向肿瘤相关巨噬细胞的全身性树状聚合物递送可改善原位胶质母细胞瘤的预后

胶质母细胞瘤是原发性脑癌的最常见和侵袭性形式，中位生存期为16-20个月，五年生存率<5％。免疫疗法的最新进展表明，通过靶向肿瘤相关巨噬细胞（TAMs）的集落刺激因子1（CSF-1）信号通路来解决肿瘤的免疫问题，具有改善胶质母细胞瘤治疗的潜力。然而，这种疗法在临床翻译中显示出有限的成功，部分是由于在实体瘤中缺乏特异性靶向细胞和全身毒性。在这项研究中，我们提出了一种新型的羟基树状大分子介导的免疫疗法，可以将CSF-1R抑制剂BLZ945（D-BLZ）从全身性给药选择性地递送至胶质母细胞瘤脑肿瘤中的TAM，从而以局部方式重新极化肿瘤免疫环境。我们显示，BLZ945与树状聚合物的缀合可以在细胞内和肿瘤内条件下持续释放。我们证明了针对TAM的单一系统剂量D‐BLZ降低了TAM中的肿瘤表达并促进了细胞毒性T细胞的浸润，与游离的BLZ945相比，可延长生存期并减轻疾病负担。我们的结果表明，树状大分子-药物偶联物可以通过选择性地将免疫疗法传递至TAMs，从而促进全身性肿瘤免疫应答的特异性，局部操作，从而提高治疗效果，同时降低脱靶效应。我们证明了针对TAM的单一系统剂量D‐BLZ降低了TAM中的肿瘤表达并促进了细胞毒性T细胞的浸润，与游离的BLZ945相比，可延长生存期并减轻疾病负担。我们的结果表明，树状大分子-药物偶联物可以通过选择性地将免疫疗法传递至TAMs，从而促进全身性肿瘤免疫应答的特异性，局部操作，从而提高治疗效果，同时降低脱靶效应。我们证明了针对TAM的单一系统剂量D‐BLZ降低了TAM中的肿瘤表达并促进了细胞毒性T细胞的浸润，与游离的BLZ945相比，可延长生存期并减轻疾病负担。我们的结果表明，树状大分子-药物偶联物可以通过选择性地将免疫疗法传递至TAMs，从而促进全身性肿瘤免疫应答的特异性，局部操作，从而提高治疗效果，同时降低脱靶效应。