The Dichotomy of Tumor Control by Recruited and Resident Tumor-Associated Macrophages.

Tumor-associated macrophages (TAMs) play dual roles in cancer, either promoting or suppressing tumor progression, complicating therapeutic approaches. TAMs include recruited macrophages (recMacs), derived from circulating monocytes, and tissue-resident interstitial macrophages (IMs). We recently identified a heterogeneous population of chemokine-expressing IMs, including subsets that support tertiary lymphoid structure (TLS) formation during lung inflammation. Here, we show that IMs can be either pro- or anti-tumorigenic, depending on the subset. Using Pf4ᶜʳᵉCx3cr1ᴰᵀᴿ mice to deplete CD206hi IMs expressing Cxcl13, Cxcl9, and Cxcl10, we demonstrate their essential role in TLS formation, lymphocyte recruitment, and tumor suppression in melanoma and lung adenocarcinoma. In contrast, Ccl2-expressing IMs promote tumor growth by recruiting pro-tumorigenic recMacs. Spatial transcriptomics confirmed the distinct localization and chemokine profiles of these subsets. Finally, CCR5 blockade with the FDA-approved inhibitor Maraviroc during neoantigen vaccination improved tumor control by preventing the migration of immunosuppressive, antigen-presenting recMacs (moDCs). These findings support the development of macrophage-targeted therapies by identifying pro-tumorigenic subsets and recMac trafficking as actionable targets, while preserving macrophage populations that sustain anti-tumor immunity.