Extending the findings in nonbrain tumor models showing that GPNMB binds to its receptor CD44 on cancer cells to promote stemness via upregulating IL-33 (46), our studies reveal an additional mechanism: that CD44 functions as a GPNMB receptor and mediates GPNMB’s stemness-promoting effect via activating the PYK2/RSK2 signaling pathway. Here, GPNMB is linked to cancer.