Chemokine-defined macrophage niches establish spatial organization of tumor immunity

Macrophages are among the most abundant immune cells in solid tumors, yet how macrophage lineage and spatial organization shape antitumor immunity remains unclear. Here we uncovered a division of labor between tissue-resident CD206^hi and CD206^lo interstitial macrophage (IM) subsets and Ly6c2⁺Fn1⁺Vcan⁺ recruited macrophages (recMacs) in lung cancer. Using single-cell and spatial transcriptomics, we identified chemokine-expressing IM subsets with opposing functions. Cxcl13⁺CD206^hi IMs, Cxcl9⁺CD206^hi IMs and Cxcl10⁺CD206^hi IMs positioned along bronchovascular regions drove tertiary lymphoid structure formation, lymphocyte recruitment and tumor control, whereas Ccl2⁺ IMs, localized within tumor regions, recruited protumorigenic Ly6c2⁺Fn1⁺Vcan⁺ recMacs. In addition, Ly6C⁺CD11b⁺ monocyte-derived dendritic cells (moDCs) functioned as immunosuppressive antigen-presenting cells in tumor-draining lymph nodes. During neoantigen vaccination, CCR5 blockade with maraviroc selectively inhibited antigen-bearing moDC migration, enhancing dendritic cell-mediated antitumor immunity. These findings showed how macrophage lineage and spatial compartmentalization govern tumor immunity and identified strategies to preserve protective IM functions, while disrupting macrophage-driven immunosuppression.