Cells sense the biophysical properties of the tumor microenvironment (TME) and adopt these signals in their development, progression, and metastatic dissemination. Recent work highlights the mechano-responsiveness of cells in tumors and the underlying mechanisms. Furthermore, approaches to mechano-modulating diverse types of cell have emerged aiming to inhibit tumor growth and metastasis. These include targeting mechanosensitive machineries in cancer cells to induce apoptosis, intervening matrix stiffening incurred by cancer-associated fibroblasts (CAFs) in both primary and metastatic tumor sites, and modulating matrix mechanics to improve immune cell therapeutic efficacy. This review is envisaged to help scientists and clinicians in cancer research to advance understanding of the cellular mechano-responsiveness in TME, and to harness these concepts for cancer mechanotherapies.