Solid tumors develop elevated mechanical stresses and microenvironmental abnormalities that impair perfusion and hinder the transport of therapeutic agents, reducing treatment effectiveness and contributing to tumor progression and resistance. Ultrasound sonopermeation combined with vascular normalization, as well as focused ultrasound induced hyperthermia with temperature sensitive liposomes are promising strategies to enhance vascular function and drug delivery, yet a unified quantitative framework capturing their combined effects remains limited. To address this gap, we developed an integrated multiphysics computational model that links mechanical stress modulation, acoustic propagation, tissue heating and thermally triggered nanocarrier release. The model incorporates key biological and vascular components involved in tumor progression, including tumor and immune cells, endothelial cells, angiopoietins and vascular endothelial growth factor. Using this framework, we identified optimal conditions for combining vessel normalization agents with sonopermeation to improve nano-immunotherapy, achieving strong agreement with published experimental data. Parametric analysis showed that acoustic pressures of 0.24–0.27 MPa and a mechanical index of 0.17 maximized drug delivery and reduced tumor volume, consistent with clinically relevant sonopermeation settings. The model also captured focused ultrasound hyperthermia combined with temperature sensitive liposome therapy, integrating acoustic heating and temperature dependent drug release, with predictions matching published tumor growth data. Sensitivity analysis indicated that ultrasound exposure duration, treatment timing, drug release kinetics and liposome size strongly influence therapeutic outcomes. Intermediate liposomes (~50 nm radius) were optimal under moderate vascular permeability, whereas larger liposomes (~65 nm) were more effective in highly permeable tumors. Overall, this unified framework enables quantitative optimization of ultrasound assisted therapeutic strategies and supports the development of more effective combination treatments for solid tumors.