Spatial and functional organization of single cells in their tissue context is essential for a true mechanistic understanding of novel biology and disease pathogenesis, which is often missing in current single-cell omics data. In addition, the structure and function of three-dimensional multicellular tissues depend critically on the spatial and temporal coordination of molecular and physical properties in cells, yet the organizational principles that govern these events and their disruption in disease remain largely obscured due to the limitations of existing methods. Here, I propose to develop new tools to co-profile biomechanical and biochemical changes in cells in a spatially resolved manner. This work will advance our understanding of mechanotransduction mechanisms in the tissue context and enable potential applications for disease diagnostics and therapeutics.