Soubhik Ghosh, Xin Li, Kavita Rawat, Aishwarya Dighal, Stephanie Kalinowski, Reza Hosseini, Fred Kolling, Carol S. Ringelberg, Claudia Jakubzick
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 CD206hi and CD206lo 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+CD206hi IMs, Cxcl9+CD206hi IMs and Cxcl10+CD206hi 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. Jakubzick and colleagues show that the tumor microenvironment is shaped by opposing programs in tissue-resident CD206hi and CD206lo interstitial macrophages and Ly6c2+Fn1+Vcan+ recruited macrophages, various macrophage subsets that are spatially segregated and mechanistically distinct.