Environmentally induced cell stiffening shapes metastatic site selection by tuning the immune vulnerability of cancer cells

Metastatic microenvironments vary widely not only in their biochemical composition but also in their mechanical properties. Here, we examined how the mechanical rigidity of the metastatic niche affects metastases seeding and the local efficacy of antitumor immunosurveillance. Cancer cells stiffened in response to increasing environmental rigidity, a biophysical change that mechanically sensitized them to killing by cytotoxic lymphocytes. In immunodeficient mice, rigidity sensing by cancer cells yielded robust bone colonization, accompanied by marked stiffening of the cancer cells themselves. Conversely, in immunocompetent hosts, stiffer cancer cells were selectively eliminated, and bone metastasis was suppressed. In patients, metastatic cell stiffness was associated directly with environmental rigidity and inversely with immune infiltration. Expression of Spp1, encoding the secreted glycoprotein osteopontin, defined a subset of cancer cells that expanded in the bone, and deletion of Spp1 limited environmentally induced cancer cell stiffening, bone colonization, and immune vulnerability. Thus, environmental mechanosensing regulates both metastases seeding and antitumor immunity, providing an immunological basis for metastatic site selection.