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

Macrophages are among the most abundant immune cells in solid tumors, yet how their diverse origins and spatial organization shape anti-tumor immunity remains unclear. Here, we uncover a fundamental division of labor between tissue-resident interstitial macrophage (IM) subsets and recruited macrophages (recMacs) in lung cancer. Using single-cell and spatial transcriptomics, we identify chemokine-defined IM subsets with opposing functions: Cxcl13-, Cxcl9-, and Cxcl10-producing CD206hi IMs positioned along bronchovascular regions drive tertiary lymphoid structure formation, lymphocyte recruitment, and tumor control, whereas Ccl2-expressing IMs localize within tumor regions and recruit pro-tumorigenic recMacs. We further show that recMac-derived moDCs function as immunosuppressive antigen-presenting cells in draining lymph nodes. During neoantigen vaccination, CCR5 inhibition with Maraviroc selectively blocks antigen-bearing monocyte but not dendritic cell migration, thereby enhancing dendritic cell-mediated tumor immunity. These findings reveal how macrophage ontogeny and spatial compartmentalization govern tumor immunity and point to therapeutic strategies that preserve protective IM functions while disrupting recMac-driven immunosuppression.