Systems and methods for histotripsy and immunotherapy are provided. In some embodiments, histotripsy can be applied to a target tissue volume to lyse and solubilize the target tissue volume to release tumor antigens. In some embodiments, an immune response of the treatment can be evaluated. In other embodiments, an immune therapy can be applied after applying the histotripsy. In one embodiment, the lysed and solubilized cells can be extracted from the tissue. The extracted cells can be used to create immune therapies, including vaccines.