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

## TL;DR

Targeted therapies for melanoma can create a physical barrier that blocks immune cells, but this barrier can be reversed to improve treatment outcomes.

## Contribution

The study identifies ECM remodeling as a transient immune barrier during residual melanoma and shows that inhibiting collagen can restore immune cell access.

## Key findings

- ECM remodeling during residual disease physically excludes CD8⁺ T cells from tumor niches.
- Pharmacologic inhibition of collagen restores CD8⁺ T cell infiltration and delays resistance.
- Human melanoma datasets show an inverse correlation between collagen and T cell infiltration.

## 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.

BRAF/MEK inhibition promotes extracellular matrix (ECM) accumulation and remodeling during therapy‐tolerant residual disease, limiting CD8⁺ T cell access to tumor cells. Targeting ECM accumulation restores CD8⁺ T cell infiltration, enhances their intratumoral distribution, and delays therapeutic resistance. These findings identify ECM remodeling as a critical barrier to antitumor immunity during targeted therapy in melanoma.