Nanodrug simultaneously regulates stromal extracellular matrix and glucose metabolism for effective immunotherapy against orthotopic pancreatic cancer

The extremely dense stromal extracellular matrix (ECM) and low glucose level affect the infiltration and effector functions of antitumor immune cells, respectively, which remain two concurrent main hurdles for achieving effective immunotherapy in pancreatic tumor. It has been found that the C-X-C motif chemokine ligand 1 (CXCL1) gene negatively regulates the stromal ECM formation, while the glucose transporter 1 (GLUT1) gene mediates aberrant glucose metabolism to restrict the glucose supply to antitumor immune cells. Here, in order to restore the anti-tumor immunity for effective immunotherapy against the pancreatic tumor, a pH-sensitive and mesothelin-targeting nanodrug incorporating CXCL1 siRNA and PI3K signaling inhibitor wortmannin (WT) was prepared. Owing to its unique structural design, the nanodrug showed advantages to accumulate in and penetrate the orthotopic pancreatic tumor. Consequently, silencing the CXCL1 gene inhibited the stromal ECM formation to promote tumor infiltration of antitumor immune cells, and suppressing GLUT1 through PI3K inhibition blocked the glycolysis of cancer cells and tumor-associated macrophages (TAMs) to increase the intratumor glucose level for sustained effector functions of antitumor immune cells. In murine orthotopic pancreatic tumor model, this multifunctional nanodrug mediated strong synergistic effect of CXCL1 siRNA and WT to remodel the unfavorable tumor immunosuppressive microenvironment (TME), which dramatically boosted the therapeutic efficacy of immune checkpoint blockade in this highly malignant and immunologically “cold” tumor.