Supramolecular hosts with flexible and controllable shapes offer the prospect of generating new technologies, for example in selective chemical purifications. However, balancing flexibility with the rigidity and fidelity required for successful assembly and guest recognition needed for purification applications remains challenging. Here we report a Zn4L4 tetrahedral cage that interconverts between four diastereomers, driven by binding different guest molecules. The truxene-based cage backbone features inward-pointing methyl groups that enclose guests and differentiate the cavities of otherwise similar diastereomers. The cage switches quantitatively between two T-symmetric diastereomers when exposed to adamantane in varying stoichiometry, and adopts C3-or C2-symmetric diastereomers in the presence of lower-symmetry guests. Cyclic ion-mobility mass spectrometry (cIMS-MS) provided insights into the structure and dynamics of these diastereomeric host-guest complexes, indicating that the cage can retain its stereochemistry following guest release. We leveraged this "shape-memory" effect to achieve the programmable binding of different guests from a mixture, as controlled by pre-programmed host stereochemistry.