The occurrence of BoM results in a “cold” tumor microenvironment [37], including fewer tumor infiltration lymphocytes (especially cytotoxic T cells), osteoclastogenesis and release of pro-tumor growth factors that would form a loop between immunosuppressive cells and BoM cells [38], which renders tumors less responsive to PD-1 immunotherapy [39] and consequently worse outcomes [40]. Here, GRHL2 is linked to neoplasm.