Targeted SPP1 Inhibition of Tumor-Associated Myeloid Cells Effectively Decreases Tumor Sizes

  • Adv Sci (Weinh). 2025 Jan;12(4):e2410360. doi: 10.1002/advs.202410360.
Benan Kartal  1 ,  Christopher S Garris  1 ,  Hyung Shik Kim  1 ,  Rainer H Kohler  1 ,  Jasmine Carrothers  1 ,  Elias A Halabi  1 ,  Yoshiko Iwamoto  1 ,  Anne-Gaëlle Goubet  2  3 ,  Yuxuan Xie  2  3 ,  Pratyaksha Wirapati  2  3 ,  Mikaël J Pittet  2  3  4 ,  Ralph Weissleder  1  5
Affiliations
  • 1. Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA, 02114, USA.
  • 2. Department of Pathology and Immunology, University of Geneva, Geneva, 1211, Switzerland.
  • 3. AGORA Cancer Research Center, Swiss Cancer Center Leman, Lausanne, 1011, Switzerland.
  • 4. Ludwig Institute for Cancer Research, Lausanne, 1005, Switzerland.
  • 5. Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, MA, 02115, USA.
PMID: 39639496 DOI: 10.1002/advs.202410360
Abstract

Secreted phosphosprotein 1 (SPP1)High 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.

Keywords
SPP1; cancer; macrophage; nanoparticles.
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