Fibroblast-driven matrix remodeling shapes immune exclusion in lung cancer

Abstract

The lung tumor microenvironment (TME) is shaped by reciprocal interactions among cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), immune cells, endothelial cells, and tumor cells. Available evidence supports an integrated sequence in which tumor-derived factors, chronic tissue injury, inflammatory cytokines, and mechanical stress generate context-dependent CAF states. Matrix-producing CAFs subsequently deposit, align, and crosslink fibrillar collagen, whereas inflammatory and antigen-presenting CAF programs regulate chemokine gradients, myeloid-cell recruitment, and local T-cell responses. These structural and biochemical changes converge to reduce vascular perfusion, restrict lymphocyte movement from stromal regions into malignant-cell nests, and promote functional immune suppression, thereby contributing to resistance to immune checkpoint blockade. The supporting evidence has been obtained from complementary systems, including single-cell and spatial profiling of human lung tumors, live imaging of human lung tumor slices, primary fibroblast-tumor cell co-cultures, three-dimensional collagen or organoid models, orthotopic xenografts, and immune-competent murine lung cancer models. Because each platform captures only part of the CAF-ECM-immune axis, conclusions should distinguish clinical association from causal evidence and specify the biological system in which a mechanism was demonstrated. Stromal signatures, collagen architecture, and spatial immune-exclusion patterns may complement tumor-intrinsic biomarkers, but their utility for treatment selection remains investigational and requires analytical standardization and prospective validation. Therapeutic development may therefore prioritize phenotype-selective CAF reprogramming and functional matrix normalization over indiscriminate fibroblast depletion, while recognizing that no single stromal feature is currently sufficient to direct clinical management. Importantly, CAF activation and ECM deposition are not uniformly tumor promoting: depending on disease stage, fibroblast state, collagen topology, and immune context, selected stromal programs may physically contain early lesions or support local immune organization. This context dependence further supports cautious, biomarker-informed evaluation of stromal interventions rather than generalized depletion. Throughout this review, spatial co-occurrence and neighborhood enrichment are treated as hypothesis-generating associations unless they are supported by temporally resolved, cell-specific perturbation and rescue experiments.