Listening to Immunotherapy – Ultrasound and Photoacoustic Imaging Strategies to Guide and Enhance Cancer Treatments

Immunotherapies are transformative strategies in modern oncology, utilizing the body's own immune system to stimulate and enhance the antitumor immune response. Successful immunotherapies require precise delivery, real-time monitoring of immune reactions, and flexible treatment strategies that can adapt to patient-specific complexities. These conditions underscore the need for noninvasive, longitudinal imaging approaches to understand therapy progress and maximize response towards precision immunotherapies. Photoacoustic (PA) imaging, especially when integrated with ultrasound (US), is a powerful modality that is gaining momentum in the immunoimaging space. PA imaging enables label-free assessment of functional biological parameters using endogenous chromophores, while engineered exogenous contrast agents extend its capabilities for molecular and cellular imaging towards theranostic applications. These advances allow visualization of immune activity, therapeutic distribution, and treatment-induced microenvironmental changes in real-time. In this review, we focus on the integral role of US/PA imaging in guiding, optimizing, and advancing cancer immunotherapy. This review begins by outlining label-free imaging techniques and the use of exogenous contrast agents as theranostic nanoplatforms in cancer immunotherapies. Following this foundation, we explore US/PA imaging in immunotherapies, emphasizing photoimmunotherapy, adoptive cell immunotherapy, immune checkpoint blockade, and focused ultrasound mediated immunomodulation. Additionally, we highlight complementary multimodal imaging approaches that expand the scope of US/PA guided immunotherapy. Finally, we address key translational challenges, emerging innovations, and future directions for translating US/PA into routine clinical practice.