Kartal Benan, Garris Christopher S, Kim Hyung Shik, Kohler Rainer H, Carrothers Jasmine, Halabi Elias A, Iwamoto Yoshiko, Goubet Anne-Gaëlle, Xie Yuxuan, Wirapati Pratyaksha, Pittet Mikaël J, Weissleder Ralph
Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA, 02114, USA.
Department of Pathology and Immunology, University of Geneva, Geneva, 1211, Switzerland.
Adv Sci (Weinh). 2025 Jan;12(4):e2410360. doi: 10.1002/advs.202410360. Epub 2024 Dec 5.
Secreted phosphosprotein 1 (SPP1) tumor-associated macrophages (TAM) are abundant tumor myeloid cells that are immunosuppressive, pro-tumorigenic, and have a highly negative prognostic factor. Despite this, there is a lack of efficient TAM-specific therapeutics capable of reducing SPP1 expression. Here, on a phenotypic screen is reported to identify small molecule SPP1 modulators in macrophages. Several hits and incorporated them into a TAM-avid systemic nanoformulation are identified. It is shown that the lead compound (CANDI460) can down-regulate SPP1 in vitro and in vivo and lead to tumor remissions in different murine models. These findings are important as they offer a promising avenue for developing novel therapeutic strategies targeting TAM.
分泌性磷蛋白1（SPP1）肿瘤相关巨噬细胞（TAM）是丰富的肿瘤髓样细胞，具有免疫抑制、促肿瘤发生的特性，并且是一种高度负面的预后因素。尽管如此，目前缺乏能够降低SPP1表达的有效TAM特异性疗法。在此，据报道通过表型筛选来鉴定巨噬细胞中的小分子SPP1调节剂。鉴定出了几种活性化合物，并将它们整合到一种对TAM有亲和力的全身纳米制剂中。结果表明，先导化合物（CANDI460）在体外和体内均可下调SPP1，并在不同的小鼠模型中导致肿瘤缓解。这些发现很重要，因为它们为开发针对TAM的新型治疗策略提供了一条有前景的途径。
