Suppressing\nPancreatic Cancer Survival and Immune\nEscape via Nanoparticle-Modulated STING/STAT3 Axis Regulation

Pancreatic ductal adenocarcinoma\n(PDAC) poses a challenge\nin oncology\ndue to its high lethality and resistance to immunotherapy. Recently,\nemerging research on the stimulator of interferon gene (STING) pathway\noffers novel opportunities for immunotherapy. Although STING expression\nis retained in PDAC cells, the response of PDAC cells to STING agonists\nremains ineffective. Signal transducer and activator of transcription\n3 (STAT3), a downstream pathway of STING, is notably overexpressed\nin pancreatic cancer and related to tumor survival and immune escape.\nWe observed that inhibiting STAT3 signaling post-STING activation\neffectively suppressed tumor growth through signal transducer and\nactivator of transcription 1 (STAT1)-mediated apoptosis but led to\na potential risk of immune-related adverse events (irAEs). To address\nthis issue, we designed a tumor-penetrating liposome for the codelivery\nof STING agonist and STAT3 inhibitor. These nanoparticles regulated\nthe STING/STAT3 signaling axis and effectively inhibited the proliferation\nand survival of tumor. Simultaneously, we found a significant increase\nin the activation of NK cells and CD8<sup>+</sup> T cells after treatment,\nleading to robust innate immunity and adaptive immune response. We\nhighlight the potential of regulating the STING/STAT3 axis as a promising\ntreatment for improving clinical outcomes in PDAC patients.