Stromal Defense Against Cancer: An Unprecedented Mechanism Limiting Cancer Invasion Into the Bone

Decades of research into the immune regulation of cancer have revolutionized oncology, leading to the clinical success of immune checkpoint inhibitors. In contrast, the roles of nonimmune systems in tumor regulation remain largely undefined. Our recent study of cancer bone invasion has uncovered a previously unrecognized host defense mechanism: stromal cells in the periosteum, the membranous tissue enveloping the bone, actively respond to tumor proximity and facilitate periosteum thickening that physically impedes tumor invasion into the bone. We propose a new concept, "stromal defense against cancer (SDAC)," a unique mechanism of tumor regulation orchestrated by stromal cells. In this review, we summarize the molecular and cellular mechanisms underlying SDAC and discuss its clinical implications.