Cancer-associated fibroblasts promote immune evasion in pancreatic cancer via miR-181b-5p/STING/LGALS1 pathway.

Pancreatic cancer remains one of the deadliest malignancies, characterized as a natural "immune desert". Despite the remarkable advances of cancer immunotherapy in recent years, it shows minimal efficacy in this cancer type. Cancer-associated fibroblasts (CAFs) play a crucial role in pancreatic cancer progression and immune regulation. Although their clinical potential has garnered significant attention, their specific functions and underlying mechanisms remain poorly defined. Here, we elucidate a mechanism by which CAFs reprogram PC cells to suppress CD8+ T cells. We found that CAFs enhance the CD8+ T cell-suppressive function of PC cells in vitro, and CAFs drive tumor progression by reduced and dysfunctional CD8+ T cells in vivo. Mechanistically, CAF-derived miR-181b-5p targets SEC24C (a key transporter for the STING) in PC cells to inhibit the STING phosphorylation. The inhibition of STING phosphorylation blocks YY1 nuclear translocation, thereby de-repressing SUSD2 and LGALS1 transcription. The upregulated LGALS1 is then secreted via SUSD2 assistance, ultimately suppressing CD8+ T cell function and inducing apoptosis. Our findings define a stromal-immune axis in pancreatic cancer, linking miR-181b-5p from CAFs to the establishment of an immune-suppressive niche via the STING pathway in tumor cells, thereby revealing this cascade as a targetable mechanism to counteract immune evasion.