Unexpectedly, we discover that NK-LAAO-treated cancer cells deploy a defense mechanism by amplifying the prominent expression of the pleiotropic cytokine IL-6 via the Panx1/iCa2+ signaling pathway to induce the expressions of antiapoptotic and antioxidant genes, which hamper the effectiveness of NK-LAAO in killing cancer cells. Here, PANX1 is linked to cancer.