<p>Precision oncology critically depends on two fundamental pillars: preclinical models that faithfully recapitulate tumor heterogeneity and the tumor microenvironment (TME), and therapeutic strategies that enable spatiotemporally controlled, highly efficient, and non-invasive intervention. Patient-derived tumor organoids (PDTOs) address the former by preserving the genomic landscape, histopathological features, and key cellular components of the original TME. Concurrently, ultrasound-responsive nanomaterials offer unprecedented therapeutic controllability through unique activation mechanisms, deep tissue penetration, and on-demand triggering of drug release or multimodal therapeutic effects (e.g., sonodynamic, sono-thermal, and mechanical effects). This review is the first to systematically explore the novel paradigm emerging from the deep integration of these two frontier fields. We begin with an in-depth analysis of the design principles of ultrasound-responsive nanomaterials and their diverse bio-responsive mechanisms, elucidating how functional modifications enable precise targeting of the complex PDTOs microenvironment. We then focus on the fundamental advantages of PDTOs as an evaluation platform over conventional models, particularly in simulating drug penetration barriers, heterogeneity of therapeutic response, and the efficacy of combination therapies, especially immunotherapy. Finally, we provide a critical analysis of the current challenges and a forward-looking perspective on future directions. The synergistic innovation between tumor organoids and ultrasound-responsive nanomedicine is paving a robust new path for precision oncology, facilitating the crucial transition from a “patient-derived in vitromodel” to “patient-specific therapy”.</p>