Evidence from physical sciences in oncology increasingly suggests that the interplay between the biophysical tumor microenvironment and genetic regulation has significant impact on tumor progression. Especially, tumor cells and the associated stromal cells not only alter their own cytoskeleton and physical properties but also remodel the microenvironment with anomalous physical properties. Together, these altered mechano-omics of tumor tissues and their constituents fundamentally shift the mechanotransduction paradigms in tumorous and stromal cells and activate oncogenic signaling within the neoplastic niche to facilitate tumor progression. However, current findings on tumor biophysics are limited, scattered, and often contradictory in multiple contexts. Systematic understanding of how biophysical cues influence tumor pathophysiology is still lacking. This review discusses recent different schools of findings in tumor biophysics that have arisen from multi-scale mechanobiology and the cutting-edge technologies. These findings range from the molecular and cellular to the whole tissue level and feature functional crosstalk between mechanotransduction and oncogenic signaling. We highlight the potential of these anomalous physical alterations as new therapeutic targets for cancer mechanomedicine. This framework reconciles opposing opinions in the field, proposes new directions for future cancer research, and conceptualizes novel mechanomedicine landscape to overcome the inherent shortcomings of conventional cancer diagnosis and therapies.