New Gene Regulator Could Revive Immune System Response in Cancer Management

A gene regulator best known for its role in bone development is now emerging as a potential lever to restore immune responses in cancer patients who stop benefiting from immunotherapy. New findings from Taiwan suggest that blocking this regulator, RUNX2, may help worn-down immune cells regain their ability to fight tumors.

National Taiwan University and National Taiwan University Hospital researchers identified RUNX2 as a key factor behind immune exhaustion in liver cancer. Their work points to RUNX2 as a driver of why immune checkpoint inhibitors, once effective, can lose their impact over time. Immune checkpoint inhibitors are designed to unleash CD8 T cells, the immune system’s main weapon against cancer.

By removing molecular restraints, these drugs allow T cells to attack tumors more aggressively. However, the problem is a lack of durability. With sustained activation, many T cells gradually lose strength and enter a dysfunctional state known as T-cell exhaustion. When that happens, tumors can regain ground.

The Taiwanese team used single-cell multiomics tools to track this decline in detail. By analyzing both gene activity and chromatin structure in individual immune cells, they followed CD8 T cells as they shifted from active killers to terminally exhausted cells during prolonged anti-PD-1 treatment.

RUNX2 activity rose steadily along this path, with patient data reinforcing the pattern. Tumor samples from liver cancer patients who failed to respond to immunotherapy showed a much higher share of exhausted T cells expressing RUNX2 compared with those who benefited from treatment. This suggested RUNX2 was pushing T-cells into exhaustion and making them less effective.

To test that idea, the researchers blocked RUNX2 using a small-molecule inhibitor. In lab cultures and mouse models where immunotherapy resistance had already developed, suppressing RUNX2 helped exhausted T cells recover their cancer-killing function. Tumor growth slowed significantly, even without restarting checkpoint therapy. Professor Hsueh-Fen Juan of National Taiwan University, who co-led the research, said the results position RUNX2 as a strong candidate for future immunotherapy combinations.

She explained that targeting this pathway could help prevent immune burnout or reverse it after resistance emerges. The findings also shift how immunotherapy resistance is understood. Rather than viewing treatment failure solely as tumors finding ways to evade detection, the study highlights changes happening inside the immune system itself. Over time, immune cells can be reprogrammed by RUNX2 into less effective states, undermining even the most advanced therapies.

Beyond treatment strategies, RUNX2 may also serve as a warning signal. Measuring its activity could help identify patients who are more likely to lose responsiveness to immunotherapy, allowing clinicians to adjust treatments earlier. The study was published in Molecular Cancer and adds to growing efforts to make cancer immunotherapy durable and effective over the long term.

With immense human and financial resources being directed by firms like Calidi Biotherapeutics Inc. (NYSE American: CLDI) into studying how immunotherapy can be improved to help a lot more cancer patients, this study provides further proof that cancer treatment is set for a major transformation over the coming years.

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