Decoding the CAF–TAM axis: multi-omics dissection and therapeutic targeting of stromal–immune crosstalk in the tumor microenvironment

Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) are pivotal stromal and immune components of the tumor microenvironment (TME) that orchestrate immune evasion, metabolic reprogramming, and therapeutic resistance. Regions enriched in CAFs are frequently accompanied by dense TAM infiltration, underscoring their close structural and functional interdependence. Recent advances in single-cell, multi-omics, and spatial profiling technologies have revolutionized our understanding of the spatiotemporal heterogeneity, lineage evolution, and bidirectional signaling between CAFs and TAMs. In this review, we summarize the latest progress from transcriptomic, epigenomic, metabolomic, and spatial multi-omics studies, highlighting the diverse CAF/TAM subpopulations, their intercellular communication networks, and their collective roles in extracellular matrix remodeling, immune suppression, metabolic adaptation, and angiogenesis. Finally, we discuss emerging therapeutic strategies targeting CAFs, TAMs, and their interactive pathways, offering new conceptual and translational insights into reprogramming the immunosuppressive TME and enhancing antitumor efficacy.