SUMMARY

Ultrasound-mediated thermal stress is a promising strategy for treating brain cancer, providing a unique approach to targeted intervention. In contrast to high-temperature focal hyperthermia and ablation therapy causing direct cell destruction, our focus on mild hyperthermia (38 – 42 °C) offers a spatiotemporal method for brain cancer targeting. Despite indications from studies in peripheral tumors that mild hyperthermia can modify the tumor microenvironment, its potential in brain cancer treatment remains largely unexplored due to challenges in safely applying hyperthermia in the brain. Through establishing a robust intracranial mild hyperthermia system and exploring its implications, this work demonstrates that FUS-mediated hyperthermia, combined with heat-sensitive anticancer agents (TSL-Dox and TS.BTE CAR T cells) can create unique opportunities for safer and more effective treatments against aggressive brain tumors. Moreover, this research by refining our understanding of thermal stress impact on the brain TME can support novel treatment paradigms.