Enhancing immune cell trafficking to brain tumors: Recent advances and therapeutic strategies

For peripheral immune cells to be effective against brain tumors, multiple coordinated steps are required, including migration and homing to the local microenvironment-collectively referred to as immune cell trafficking-followed by survival, proliferation, and persistence, all while remaining functional. This review focuses on the often-overlooked first step, trafficking, which is critical for initiating subsequent processes and driving antitumor responses. We summarize the migration cascade of immune cells, including T cells and macrophages, across the blood-brain barrier (BBB) and how primary brain tumors as well as brain metastases alter the molecular pathways and interactions associated with the immune cell migration cascade across the BBB and their functional homing. Subsequently, we highlight recent developments in engineering biomolecular, cellular, and physical methods to modulate the tumor microenvironment and improve the functional trafficking of immune cells in brain tumors. Our analysis reveals novel combinations to potentiate antitumor responses via feedforward mechanisms and modular therapeutic strategies designed to improve the migration and accumulation of functional immune cells in brain tumors. A deeper understanding of immune cell trafficking, distribution, and homing through the application of preclinical and clinical imaging techniques along with the development of in vitro/ex vivo platforms should enable new and more potent immunotherapy strategies against primary brain malignancies and brain metastases as well as accelerate their translation to the clinic.