This dissertation developed and validated an ultrasound/photoacoustic (US/PA) image-guided focused ultrasound (FUS) platform for spatiotemporal thermal control of engineered immune cells. The core contribution is a co-registered imaging–therapy workflow that delivers localized mild hyperthermia at depth while monitoring temperature-related changes for safe, repeatable dosing. A compact system using a shared imaging array streamlined alignment and supported interleaved structural ultrasound and ultrasound thermal strain imaging (TSI) during FUS exposures, enabling robust activation of thermal gene switches (TGSs) in T cells without compromising viability. To overcome tissue-composition dependence that limits quantitative thermometry, this work introduced nanoparticle-anchored PA thermometry, where an engineered interfacial microenvironment governs thermoelastic response. Finally, the approach was integrated in vivo in a solid-tumor model using gold nanoassemblies as PA contrast agents and as labels for TGS-engineered T cells, demonstrating lipid-independent PA sensitivity and localized reporter expression following US/PA-guided FUS heating.