Pharmacological Polarization of Tumor‐Associated Macrophages Toward a CXCL9 Antitumor Phenotype

Tumor‐associated macrophages (TAM) are a diverse population of myeloid cells that are often abundant and immunosuppressive in human cancers. CXCL9Hi TAM has recently been described to have an antitumor phenotype and is linked to immune checkpoint response. Despite the emerging understanding of the u...

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Bibliographic Details
Published in:Advanced science 2024-04, Vol.11 (15), p.e2309026-n/a
Main Authors: Enbergs, Noah, Halabi, Elias A., Goubet, Anne‐Gaëlle, Schleyer, Kelton, Fredrich, Ina R., Kohler, Rainer H., Garris, Christopher S., Pittet, Mikaël J., Weissleder, Ralph
Format: Article
Language:English
Subjects:
Animals
Bone marrow
Chemokine CXCL9 - metabolism
Chemokine CXCL9 - therapeutic use
Chemokines
CXCL9
Cytokines
Drug delivery systems
Drug dosages
Flow cytometry
Genotype & phenotype
Humans
IFNg
Interferon
macrophage
Macrophages - metabolism
Mice
nanoparticles
Neoplasms - pathology
PARP7
Phenotype
polarization
STING
Toxicity
Tumor-Associated Macrophages
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Summary:Tumor‐associated macrophages (TAM) are a diverse population of myeloid cells that are often abundant and immunosuppressive in human cancers. CXCL9Hi TAM has recently been described to have an antitumor phenotype and is linked to immune checkpoint response. Despite the emerging understanding of the unique antitumor TAM phenotype, there is a lack of TAM‐specific therapeutics to exploit this new biological understanding. Here, the discovery and characterization of multiple small‐molecule enhancers of chemokine ligand 9 (CXCL9) and their targeted delivery in a TAM‐avid systemic nanoformulation is reported. With this strategy, it is efficient encapsulation and release of multiple drug loads that can efficiently induce CXCL9 expression in macrophages, both in vitro and in vivo in a mouse tumor model. These observations provide a window into the molecular features that define TAM‐specific states, an insight a novel therapeutic anticancer approach is used to discover. A 17 nm carbohydrate drug delivery system is used to shuttle a triple combination of a PARP7 inhibitor, a TLR7/8 agonist, and a STING agonist into tumor‐associated macrophages via systemic administration. This results in high CXCL9 induction in vitro and in vivo and antitumor efficacy.
ISSN:2198-3844
2198-3844
DOI:10.1002/advs.202309026