This study reports on (i) a simple, fast, and low-cost method for generating uniform breast cancer MCTS with tunable sizes as depicted in Fig. 1A, (ii) a strategy to better mimic CD44-positive breast TME in vitro using HA-based cryogels as illustrated in Fig. 1B–C, the (iii) consequences of using inappropriate adhesion moieties in biomaterials design to develop cancer models, and (iv) the potential of cryogels as a versatile platform to recapitulate key features of aggressive breast tumors. Here, CD44 is linked to breast cancer.