Immune-stromal interactions at the crossroads of tissue injury, repair, and tumor progression.

Macrophage-fibroblast crosstalk plays a critical yet incompletely understood role in cancer, fibrosis, and tissue repair. A central challenge is capturing the diversity of these cells, whose phenotypes are shaped by microenvironmental cues and developmental origins. Macrophage heterogeneity reflects the tissue-resident and bone marrow-derived lineages, while fibroblasts adopt distinct subsets defined by tissue context. Myofibroblasts can emerge from fibroblasts, monocytes, and other stromal cells. The lack of markers to distinguish these subpopulations remains a major barrier to defining their specific roles in pathological outcomes, including tissue injury, repair, and cancer. Together, macrophages and fibroblasts maintain tissue homeostasis and drive repair; however, disruptions in their crosstalk promote fibrotic remodeling and tumor-permissive microenvironments. Here, we review the origins, diversity, and roles of non-parenchymal macrophages and fibroblasts in fibrosis and cancer, highlighting key gaps and future directions to advance the field.