The Dichotomy of Tumor Control by Recruited and Resident Tumor-Associated Macrophages 2253531

Abstract Introduction Tumor-associated macrophages (TAMs) can either promote or suppress tumor progression depending on their phenotype and localization. TAMs include monocyte-derived recruited macrophages (recMacs) and tissue-resident interstitial macrophages (IMs), but the spatial and functional diversity of IMs within the tumor microenvironment (TME) remains unclear. Methods Single-cell and spatial transcriptomic analyses were used to define macrophage heterogeneity and chemokine expression in the lung TME. Flow cytometry and immunofluorescence characterized distinct IM subsets. DC based neoantigen vaccination combined with transient CCR5 inhibition (Maraviroc) applied to assess monocyte trafficking and antigen presentation. Results Two major IM subsets were identified: CD206hi IMs expressing Cxcl9, Cxcl10, and Cxcl13 promoted tertiary lymphoid structure (TLS) formation, lymphocyte recruitment, and anti-tumor immunity, whereas Ccl2-expressing IMs recruited pro-tumor recMacs expressing Spp1, Vegfa, Arg1, and Cd274 (PD-L1), sustaining an immunosuppressive niche. Spatial transcriptomics localized Cxcl13+ IMs to bronchovascular and pleural niches near TLS sites, whereas Ccl2+ IMs and recMacs dominated tumor cores. Bone marrow chimera experiments confirmed that IM-derived CCL2, not endothelial or monocyte sources, drives recMac recruitment and tumor progression. Functionally, recMacs acted as immunosuppressive antigen-presenting cells in draining lymph nodes. Short-term CCR5 blockade with Maraviroc during dendritic cell-based neoantigen vaccination inhibited monocyte trafficking and enhanced tumor control. Conclusion Lung IMs display distinct spatial and functional roles in shaping the TME. Chemokine-producing CD206hi IMs sustain anti-tumor immunity, while CCL2-producing IMs and recMacs promote tumor growth. Targeting the CCL2—CCR2/CCR5 axis while preserving chemokine-producing IMs offers a promising strategy to augment cancer immunotherapy and neoantigen vaccine efficacy. Funding Source National Institutes of Health (NIH) grants: NIH grants R35 HL155458 (C.V.J.) National Cancer Institute Cancer Center Support Grant 5P30CA023108 (F.W.K.) NIH NIGMS P20GM130454 (F.W.K.) NIH S10 1S10OD030242 (F.W.K.) Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)