Immunotherapy Can Fuel Cancer Growth: The Dual Role of TGF-β When the “Brake” Is Released

A study found that immunotherapy may actually fuel tumor growth in some patients with cancer. The cause was the release, during treatment, of a signal that had acted as a “brake” on cancer cell growth.

On the 4th (local time), the Chinese medical news outlet BioOn reported that researchers at Northwestern University Feinberg School of Medicine published the findings in the international journal Cancer Discovery.

The researchers tested a bifunctional fusion protein called bintrafusp alfa in a clinical trial involving patients with recurrent small cell lung cancer and related neuroendocrine cancers. The drug was designed to simultaneously block the immune checkpoint PD-L1 and TGF-β signaling, which has immunosuppressive effects.

However, the results diverged sharply. Among the 34 patients whose response was evaluated, 18% had a marked reduction in tumors, while 38% experienced “hyperprogression,” in which tumors grew faster after treatment began.

Analysis of tumor tissue, blood immune cells and circulating tumor DNA before and after treatment showed that tumors with hyperprogression had abnormally active TGF-β signaling before treatment.

In functional experiments, proliferation of small cell lung cancer cell lines with intact TGF-β signaling increased significantly when the pathway was artificially blocked. By contrast, cell lines that naturally lacked the TGF-β response mechanism showed no change after the same intervention.

In other words, in certain tumors, TGF-β acts as a “brake” on cancer cell growth. By removing it, the drug allowed previously suppressed cancer cells to proliferate rapidly.

Professor Thomas said, “Blocking more immunosuppressive pathways is not always a better strategy,” adding that “in some tumors, these pathways also suppress the growth of the cancer cells themselves, so the biological context determines the outcome.”

The researchers also analyzed data from hundreds of patients who received the drug for other cancer types, including cervical cancer, nasopharyngeal cancer and non-small cell lung cancer. Hyperprogression was observed in all of these cancer types, although its frequency varied.

External independent data also showed that patients had poorer survival outcomes when their tumors had higher TGF-β transcriptional activity.

The researchers said that several TGF-β-targeted drug candidates are currently in clinical trials, and that some patients could be at risk of disease worsening unless tumors whose growth is suppressed by TGF-β are identified before treatment.