Thermal sonogenetics for adoptive cell transfer therapy

Adoptive cell transfer (ACT)-based immunotherapy has emerged as a transformative approach for treating cancer, offering durable responses through the ex vivo expansion and reinfusion of antigen-specific immune cells. Despite remarkable clinical successes, most notably with chimeric antigen receptor (CAR)-T cell therapy, ACT remains limited by severe toxicities such as cytokine release syndrome, on-target off-tumor effects, and suppression within the tumor microenvironment (TME). To address these challenges, there is growing interest in engineering immune cells with inducible gene circuits that enable spatially and temporally controlled activation. While small molecule- and light-inducible systems have demonstrated proof-of-concept control, their clinical translation is hindered by issues of pharmacokinetics, tissue penetration, and systemic exposure. Focused ultrasound (FUS) offers a non-invasive alternative capable of achieving localized and deep tissue heating, enabling precise activation of genetically engineered cells through heat-responsive promoters, a strategy termed thermal sonogenetics. This review summarizes recent advances in FUS-mediated, heat-inducible genetic control within the context of ACT-based immunotherapy. We first outline the development, successes, and limitations of current ACT platforms, including TIL, TCR-T, and CAR-T therapies, to motivate the need for controllable systems. We then discuss the use of heat shock promoters-particularly HSP70-family elements-as central components of thermal gene switches and review all benchtop and preclinical studies employing FUS for inducible gene expression in immune and non-immune cells; finally, we consider the future potential and limitations of thermal sonogenetics to enable remote, precise, and reversible control of engineered immune cells, paving the way for safer and more effective cellular immunotherapies.