Macrophages restrict tumor immune infiltration by controlling collagen topography.

During tumorigenesis, the extracellular matrix is extensively remodeled. Whereas the impact of such remodeling on tumor growth and invasion is well described, the consequences on immune infiltration are not well understood. Combining tissue imaging and machine learning, we show that immune cell localization in tumors can be predicted by the local topography of fibrillar collagens. Such topographies are dictated by a fibrotic pathway driven by transcription factor 4 (<i>Tcf4</i>) in both cancer and stromal cells, which promotes collagen III deposition and results in intermingled collagen networks that favor intratumor infiltration of T cells and neutrophils. Macrophages inhibit this pathway, highlighting their key structural role in shaping the tumor extracellular matrix. Reanalysis of data from human solid tumors revealed a strong correlation between <i>TCF4</i>, <i>COL3A1</i>, and T cell and neutrophil signatures. Together, our data identify collagen network topographies as a key regulator of tumor-infiltrating immune cells.