Fibroblast transformation in the tumor microenvironment of lung adenocarcinoma: heterogeneity, regulation, and therapeutic targeting

Cancer-associated fibroblasts (CAFs) are important stromal cells in the tumor microenvironment of lung adenocarcinoma (LUAD). This review discusses the different cellular sources of CAFs and the main signaling pathways involved in fibroblast-to-CAF transition, with attention to the biological settings that are especially relevant in LUAD. It further discusses CAF heterogeneity not only in terms of functional subtypes, but also from the perspective of dynamic cell states shaped by spatial niche, intercellular communication, and therapy-related stress. On this basis, we outline how distinct CAF states contribute to extracellular matrix remodeling, metabolic reprogramming, invasion and metastasis, angiogenesis, immunosuppression, and therapeutic resistance in LUAD. Particular attention is given to the treatment relevance of CAFs in driver-defined disease settings, where stromal programs may influence responses to targeted therapy and immunotherapy in a context-dependent manner. We also address the main obstacles to CAF-targeted strategies, particularly heterogeneity, plasticity, and functional compensation, and point to possible directions based on precise subtyping, functional modulation, and rational combination therapy. This review thus offers a LUAD-specific perspective for understanding CAF biology and for guiding more precise stromal intervention strategies.