From stiffness-softness paradox to drug delivery systems: mechanical properties and regulation in tumor progression

Tumor progression is regulated by unique mechanical properties. However, there is a "stiffness-softness paradox" between tumor tissues and tumor cells in terms of mechanical characteristics. On the one hand, abnormal stiffening of tumor tissue promotes tumor proliferation and invasion by activating mechanical related signaling pathways, promoting epithelial mesenchymal transition (EMT), affecting angiogenesis, and aggravating the immunosuppressive microenvironment; On the other hand, tumor cells themselves undergo softening, which enhances their deformability through cytoskeletal reorganization. This adaptive softening assists tumor cells escape from the primary site and transform into circulating tumor cells (CTCs). These CTCs then support their own survival in the circulatory system by forming CTC clusters, intracellular bacterial associations, or metabolic adaptations, thereby promoting distant metastasis. These mechanical characteristics of tumors are inspiring novel anti-cancer strategies aimed at targeting and normalizing mechanical abnormalities in solid tumor tissues and cells, particularly in the field of intelligent drug delivery systems (DDS). With the advantages of modifiability, targeting and controlled release, DDS offers promising approaches for modulating tumor mechanical properties. This article focuses on the distinctive mechanical characteristics of tumor tissues and cells, systematically reviews the roles of tumor tissue and tumor cell mechanical abnormalities in tumor progression, and summarizes recent advances in mechanical regulation strategies based on DDS for cancer treatment, as well as the intrinsic mechanical regulation of DDS and external mechanical triggering of drug release. Additionally, mechanical modulation methods beyond nanomedicine are discussed, providing potential directions for developing novel nano‑therapeutic strategies for mechanical regulation.