Therapy‐Induced ECM Remodeling Creates a Transient Immune Barrier in Residual Melanoma

Abstract Targeted therapies reshape the tumor not only by eliminating malignant cells but also by altering the stromal and immunologic adaptations that emerge during treatment, which remain incompletely defined. Here, extracellular matrix (ECM) remodeling is identified as a key driver of immune exclusion during the residual disease phase—a transient, therapy‐tolerant state that precedes overt resistance. Using an immune‐competent melanoma model and temporal transcriptomic profiling of tumor cells and fibroblasts, a coordinated induction of ECM‐related genes, particularly collagen, is uncovered during the development of residual disease. This remodeling creates a physical barrier that spatially excludes CD8⁺ T cells from residual tumor niches, compromising immune surveillance. Human melanoma datasets validate increased ECM gene expression and show an inverse correlation between collagen and cytotoxic T lymphocyte infiltration, as well as patient survival. Strikingly, pharmacologic inhibition of collagen deposition, administered at the point of maximal tumor regression, restores CD8⁺ T cell infiltration and delays resistance in a CD8⁺ T cell–dependent manner. These findings define residual disease as a therapeutically actionable stromal state and demonstrate that ECM modulation can overcome immune exclusion, thereby improving the durability of targeted therapy responses.