Tumor-associated fibrosis plays a role in cellular immunity across human diseases.

Abstract

Tumor-associated fibrosis is a pervasive hallmark of solid malignancies that remodels tissue architecture, biochemical signaling, and mechanical properties, thereby profoundly influencing antitumor cellular immunity across cancers. This review summarizes current understanding of the cellular and molecular drivers of fibrotic tumor stroma, highlighting heterogeneous cancer-associated fibroblast (CAF) types (myCAF, iCAF, apCAF), myofibroblasts, vascular cells and infiltrating immune cells. We further discuss the altered extracellular matrix (ECM) landscape characterized by excessive deposition and remodeling of collagens I/III, fibronectin, hyaluronan, proteoglycans, and matrix-regulating enzymes such as LOX and MMPs that collectively define desmoplasia. Particular attention is given to the signaling pathways, epigenetic programs, and metabolic regulators that initiate and sustain fibrogenesis, with the bidirectional crosstalk among tumor cells, CAFs, and immune populations that shapes immune exclusion, dysfunction, and therapeutic resistance. In addition, we review emerging experimental models and spatial multi-omics and single-cell evidence linking stromal states with immune phenotypes across pan-cancer settings. Preclinical and translational studies demonstrate that targeted ECM remodeling, CAF reprogramming, and inhibition of profibrotic signaling pathways can restore immune infiltration and enhance antitumor immunity in a context-dependent manner. This review provides a comprehensive framework for understanding how tumor-associated fibrosis regulates cellular immunity across cancers and offers insights into the development of fibrosis-targeted immunotherapeutic strategies.