Multimodal PET Defines a 'Goldilocks' Thermal Window for Focused Ultrasound Ablation and Immunotherapy Combinations.

Background: Thermally ablative focused ultrasound (T-FUS) offers a noninvasive, spatially precise strategy for local tumor destruction, with the added potential to remodel tumor architecture and immune dynamics in ways that influence downstream therapeutic delivery and efficacy. Despite promising preclinical and clinical findings, the T-FUS parameters that best balance tumor debulking with preservation of local biologic, e.g. immunotherapy, penetrance remain unclear. Thermal dose, defined by the relationship between tissue heating, exposure duration, and biological effect, is likely a critical determinant of this balance. Excessive thermal dose may eliminate the vascular and stromal features needed to support immunotherapy access, whereas insufficient thermal dose may fail to achieve meaningful cytoreduction. Here, we deploy multimodal PET, contrast-enhanced ultrasound, and tissue profiling to define a "Goldilocks Zone" for T-FUS that balances bulk tumor destruction with immunotherapy delivery. Method: Subtotal T-FUS was applied to 4T1 tumors using three thermal dose regimens resolved by Results: Conclusion: This study identifies thermal dose as a critical consideration for T-FUS immunotherapy combinations and establishes a PET-informed framework for balancing cytoreduction with therapeutic delivery. Rather than functioning solely as a local debulking modality, we demonstrate that T-FUS can be tuned to yield a post-ablation tumor state that remains accessible to large biologics. These findings provide timely, translationally relevant guidance for tailoring T-FUS regimens to achieve local tumor destruction while preserving an immunotherapy-permissive niche for combination treatment.