Cells interact with the extracellular matrix (ECM) mechanically to perform essential cell function including migration, proliferation and differentiation, which are critical in physiological processes such as development and tissue remodeling. Among the many molecules within the ECM, type I collagen and glycosaminoglycans (GAGs) are the two primary components that form the dynamic meshwork and provide structural support to cells. Mechanically, collagen sustains tension while GAGs resist compression. Extensive work has focused on how mechanics of collagen modulates cell behavior, while much less has been done to understand the roles of GAGs in cell function. In breast cancer, hyaluronic acid (HA) is overexpressed in tumor tissues, and is frequently associated with poor prognosis. We start by questioning how HA modulates cell traction force generation and tumor invasiveness within HA-rich environments using collagen- HA cogels. We find that HA significantly modifies the architecture and mechanics of the collagen fiber network, decreases tumor cells′ propensity to remodel the collagen network, decreases traction force generation and transmission distance, and attenuates tumor invasion in agreement with theoretical predictions. This work has also pinpointed that CD44, a cell surface adhesion receptor to HA, is engaged in cell traction force generation in conjunction with β1-integrin. It is also demonstrated that breast tumor invasion in HA-rich environment is CD44-dependent. Much advances on cell-based immunotherapy have been made over the past decades, however, it is still unclear how tumor mechanics may play a role in such clinical problems. In the final part of this work, we initiate a pilot study into the role of HA in immunoresistance through the lens of tumor mechanics. While modulating tumor compactness by tuning the mechanics of the tumor microenvironment (TME) has been shown to be possible, we explore the role of mechanics in immune homing as well as the effect of HA on immune killing. Traction force microscopy (TFM) data shows that the efficacy of NK killing also decreases in HA-rich environments. Strikingly, conventional flow cytometry analyses show elevated NK cytotoxicity in collagen-HA cogels despite less tumor apoptosis observed in killing assays. This work highlights the criticality of studying immune-tumor interactions in their physiological conditions, as well as the importance of the mechanical environment for immune cell killing to take place. While it is still a long way to paint the full picture of how different ECM components regulate immune-tumor interactions, our work has built a foundation for studying how solid tumors may influence the outcome of cell-based immunotherapy by priming the complex TME.