Tumor Microenvironmental Barriers to T-Cell Infiltration in Breast Cancer

Effective anti-tumor immunity depends on cytotoxic T cells entering tumors, surviving there, and maintaining effector function. However, many breast cancers, particularly hormone receptor-positive subtypes, contain relatively few infiltrating T cells. This pattern reflects a hierarchy of processes, beginning with the generation of cancer-specific T cells. Once primed in lymph nodes, T cells exit nodes and enter tumors through blood vessels. This process is controlled by endothelial adhesion molecule expression and vessel integrity. Furthermore, chemokine gradients control whether T cells infiltrate cancer cell nests or are retained in the tumor stroma. Finally, the extracellular matrix adds physical and biochemical constraints through fiber alignment, cross-linking, and matricellular proteins that can limit T-cell extravasation and intratumoral positioning. These barriers are interdependent, as extracellular matrix stiffness compresses blood vessels, disrupting adhesion molecule expression and chemokine presentation. Emerging preclinical and early clinical strategies demonstrate that vascular normalization, chemokine reprogramming, and selective extracellular matrix remodeling can improve T-cell access and sensitize tumors to checkpoint blockade. Durable clinical benefit will likely require biomarker-guided combination approaches that both enable T-cell entry and preserve their function within the suppressive tumor microenvironment.