image: Schematic showing IL-6-induced STAT3-to-PI3K signaling switch in colorectal cancer stem cells, driving ZEB1-dependent PD-L1 expression and immune evasion.
Credit: ©Science China Press
A landmark study published in Science Bulletin by researchers from the School of Medicine at Zhejiang University has unraveled how colorectal cancer stem cells (CSCs) exploit inflammatory signals to evade immune destruction. Led by Professor Jimin Shao, the research demonstrates that the cytokine interleukin-6 (IL-6) activates fundamentally distinct molecular pathways in CSCs versus differentiated cancer cells (non-CSCs) to drive immunosuppressive PD-L1 expression. This discovery not only solves a key mystery in immunotherapy resistance but also charts a path for precision combination therapies.
While IL-6 is known to promote PD-L1 expression in cancer, this study reveals unprecedented cellular heterogeneity in its mechanism. In non-CSCs, IL-6 activates the canonical JAK-STAT3-FRA1 pathway: STAT3 phosphorylation (Y705) and acetylation (K685) enable complex formation with FRA1, this complex binds CD274 promoter sites, driving PD-L1 transcription. In CSCs, a dramatic signaling switch occurs: IL-6 preferentially activates PI3K-AKT-ZEB1 signaling, bypassing STAT3. PI3K inhibition (by LY294002) blocked PD-L1 induction in CSCs but not non-CSCs. The EMT transcription factor ZEB1 binds a CD274 promoter site partially overlapping FRA1’s site.
The molecular mechanisms underlying this switch involve the enhanced activity of SHP2 phosphatase in CSCs, which redirects IL-6 signaling away from the JAK-STAT pathway and toward the PI3K-AKT cascade. Additionally, ZEB1 binding to the CD274 promoter outcompetes the STAT3-FRA1 complex, thereby explaining the dominance of this alternative pathway.
The team validated findings in 70 patient samples: High IL-6 tumors contained more PD-L1⁺/ZEB1⁺ CSCs and fewer tumor-killing T cells. When testing therapies in IL-6-humanized mice, only the triple combination (PI3K inhibitor + STAT3 inhibitor + anti-PD-L1) maximally shrank tumors by simultaneously blocking CSC/non-CSC evasion routes and restoring T-cell function.
"Targeting both pathways dismantles the immunosuppressive shield," explains corresponding author Jimin Shao. "We propose tumor tissue/blood tests for IL-6/PD-L1 to identify patients who may benefit from this approach." The team is now validating biomarkers in clinical cohorts.
About School of Medicine at Zhejiang University:
A leading medical research institution in China, focusing on mechanistic discoveries and translational therapies.
Journal
Science Bulletin