CD59 promotes pancreatic cancer progression via a tumor cell-intrinsic JAK2-STAT3 signaling axis.

Pancreatic cancer is a highly aggressive malignancy with limited therapeutic options. Although the complement system has been implicated in tumor biology, its tumor cell-intrinsic roles in pancreatic cancer remain unclear. Here, we identify the complement regulatory protein CD59 as a critical driver of pancreatic cancer progression through a cell-intrinsic signaling mechanism. CD59 is significantly upregulated in pancreatic tumors and correlates with poor patient survival. Functional assays demonstrate that CD59 promotes tumor cell proliferation and growth in vitro and in vivo, whereas its depletion suppresses these effects. Mechanistically, CD59 interacts with JAK2 to activate the JAK2-STAT3 pathway, and transcriptomic analyses identify CACNA1D as a STAT3-dependent effector mediating CD59-driven proliferation. Notably, KRAS inhibition induces compensatory activation of the CD59-JAK2-STAT3 axis, while combined targeting of CD59 or STAT3 with KRAS more effectively inhibits tumor cell growth. These findings define a tumor cell-intrinsic oncogenic function of CD59 and highlight the CD59-JAK2-STAT3-CACNA1D pathway as a potential therapeutic target in pancreatic cancer.