How the tumor microenvironment controls T-cell infiltration and CAR-T cell efficacy in solid tumors

Abstract

T-cell-based immunotherapies have transformed the treatment of several hematological malignancies, but their efficacy in solid tumors remains limited. A major obstacle is the tumor microenvironment, which restricts immune-cell trafficking, activation and persistence. Our work combines dynamic imaging of living human tumor slices with multiparametric cytometry, single-cell and spatial transcriptomics, and functional perturbations to understand these barriers directly in patient tissues. We have shown that extracellular-matrix architecture can physically constrain T-cell migration, that tumor-associated macrophages can form an additional cellular barrier to T-cell entry, and that mitochondrial metabolism is essential to sustain efficient CD8 T-cell motility and infiltration. We now apply these concepts to CAR-T cells in adult and pediatric solid tumors, including within the Cancer Grand Challenges NexTGen program. By linking CAR-T-cell behavior and activation to the cellular and structural composition of the tumor microenvironment, we aim to identify predictive biomarkers of response and rational combination strategies that improve infiltration and antitumor activity. These human ex vivo models provide a bridge between mechanistic immunology and clinical translation and may help guide the development of next-generation cellular therapies for solid cancers.