Targeted therapies achieve remarkable initial regressions in melanoma, yet nearly all patients relapse due to the emergence of drug-tolerant residual disease. Whereas most studies have compared tumors before treatment and after relapse, little is known about the tumor microenvironment during therapy itself, the critical period when residual disease develops. My dissertation addresses this gap by investigating how innate immunity and stromal remodeling shape immune accessibility under therapy and by identifying strategies to overcome these barriers.

In the first study (Chapter 2), I show that innate immune evolution, particularly natural killer (NK) cell dynamics, is central to targeted therapy response. During treatment, tumors transition from an immune-inflamed to an immune-excluded state, with declining NK infiltration and macrophage reprogramming paralleling the onset of residual disease. These findings highlight innate immunity as a dynamic driver of therapeutic outcome and suggest macrophage–NK cell interactions as actionable targets to sustain regression.

In the second study (Chapter 3), I demonstrate that targeted therapy also reprograms the stromal compartment, with extracellular matrix (ECM) remodeling, especially collagen deposition, creating transient physical barriers that restrict CD8⁺ T cell access to residual tumor niches. Inhibiting collagen deposition restored T cell infiltration and delayed resistance, underscoring ECM remodeling as a therapeutically modifiable state that limits adaptive immunity during residual disease.

Together, these studies establish that residual disease is not merely a tumor-intrinsic phenomenon but rather the coordinated outcome of evolving immune and stromal ecosystems during therapy. By focusing on the underexplored window of residual disease, this work provides new insight into how the tumor microenvironment drives relapse and identifies innate immune remodeling and ECM dynamics as tractable therapeutic axes. Ultimately, these findings support integrated approaches that target both immune and stromal barriers to extend the durability of targeted therapy in melanoma.