New study decodes how tumor “stress droplets” fuel resistance—and how to shut them down

A new study published in Science China Life Sciences reveals a critical mechanism that allows the most aggressive and common form of brain cancer, glioblastoma (GBM), to thrive in low-oxygen environments. The research identifies a promising new strategy to overcome treatment resistance by combining an existing orphan drug with standard chemotherapy.

Median survival for GBM patients has hovered at ~15 months for decades, largely because hypoxic regions spawn aggressive, drug-tolerant cells. While the HIF pathway has dominated hypoxia research, the team led by Professor Xudong Wu at Tianjin Medical University now shows that GBM also commandeers a HIF-independent circuit built around the epigenetic enzyme PRMT2.

Using single-cell imaging, biochemical dissection and patient-derived models, the researchers discovered that within minutes of oxygen deprivation, PRMT2 is sucked into membrane-less “transcriptional condensates” in the nucleus—droplets that corral the machinery needed for rapid gene activation. Once inside, PRMT2 is switched on by CDK9-mediated phosphorylation at serine-12, a modification that locks the enzyme into the droplets and enables it to place the H3R8me2a histone mark, igniting a pro-tumor transcriptional program that boosts angiogenesis and hypoxia adaptation. A naturally occurring mutation (G5S) seen in a subset of patients mimics this phosphorylation, making PRMT2 hyper-active and hyper-condensed—offering a genetic biomarker for the most aggressive tumors.

Targeting this node is straightforward. TG02, an orphan drug already tested in glioma patients, blocks CDK9 and thereby prevents PRMT2 phosphorylation and condensate formation. At nanomolar doses TG02 erased the H3R8me2a mark and silenced the hypoxia gene set.

The real payoff came in combination. Mice bearing TMZ-resistant GBM tumors received low-dose TG02 plus TMZ—a pairing that produced synergistic tumor regression and doubled survival without added toxicity. Tumor analyses showed the combo shattered the hypoxia shield, restoring TMZ sensitivity even in the tumor core.

“Our findings reveal a general principle,” Wu notes. “Transcriptional condensates can turbo-charge epigenetic enzymes, and this can be exploited pharmacologically. TG02 gives us an immediate, clinically viable way to break that cycle.” The research team is now pursuing further preclinical studies to advance this combination therapy toward clinical trials.