An Overview of TGF-? Signaling—A Dual Role in Cancer

In Robert Louis Stevenson’s novel The Strange Case of Dr. Jekyll & Mr. Hyde, Dr. Jekyll of upstanding and Mr. Hyde of evil are actually one person. In the occurrence and development of cancer, there is also such a role as both good and evil, that is, transforming growth factor? (TGF-?), which can not only inhibit the tumor progression caused by precancerous cells, but also promote the spread of tumors.

• TGF-? signaling pathway

TGF-? signaling pathway is the process of delivering a series of signals mediated by transforming growth factor. The TGF-? signaling pathway plays a key role in the growth, development, and differentiation of cells and tissues, and has important regulatory effects on cell proliferation, intercellular substance production, differentiation, apoptosis, embryonic development, and organ formation. Immune function, inflammatory response, wound repair, etc.

Among its key functions is regulation of inflammatory processes, particularly in the gut. TGF-? also plays a crucial role in stem cell differentiation as well as T-cell regulation and differentiation. As such, the abnormal expression of TGF-? and signal transduction is related to the occurrence of many diseases, such as cancer, fibrosis, and many other genetic diseases including hereditary hemorrhagic telangiectasia and family primary pulmonary hypertension.

• How does the TGF-? signaling work in cancer?

TGF-? signaling plays a key role in cancer progression. Most cancer cells can benefit from increased expression of TGF-? by affecting gene expression, immunosuppressive cytokine release, and epithelial plasticity.

It gives cancer cells invasiveness, spreadability, stem cell characteristics and resistance to treatment. TGF-? released by cancer cells, mesenchymal fibroblasts and other cells in the tumor microenvironment can create an immunosuppressive microenvironment that prevents or weakens the efficacy of anti-cancer immunotherapy by shaping the structure of the tumor and inhibiting the anti-tumor activity of immune cells, thus further promoting cancer progression. Therefore, inhibition of TGF-? signaling is considered to be one of the primary ways to enhance the efficacy of immunotherapy.

The high signal transduction activity of it has been confirmed to be related to the drug resistance of a variety of anti-cancer treatments, including chemotherapy and molecular-targeted therapy. The enhancement of TGF-? signal in tumors is also an obstacle for patients to respond to immunotherapy. It has been found that few patients who can respond to PD-1/PD-L1 antibody, CTLA-4 antibody, and CAR-T cell therapy all show lower TGF-? signals.

• Obstacles and opportunity of TGF-? signaling participating in the cancer treatment

Considering the role of TGF-? signaling in non-pathophysiological processes, it is not surprising that systemic inhibition of TGF-? signaling will accompany adverse events. Although this concern has greatly hindered the development of TGF-? inhibitors, the current early clinical trials have shown that adverse events are generally controllable, and when combined with immune checkpoint inhibitors, such therapies show significant and lasting effects.

In the future, selective targeting of TGF-? inhibitors in tumors will greatly reduce the severity of adverse events and increase treatment opportunities. The use of bispecific drugs to inhibit TGF-? or the use of drugs to interfere with the TGF-? signaling is expected to lead to new therapies. In addition, combining TGF-? inhibitors with tumor-targeting CAR-T cells, viral vectors, nanoparticles, or oncolytic viruses may provide additional opportunities. For example, CAR-T cell therapy can be engineered to convert TGF-? from an immunosuppressive cytokine to a strong stimulator of T cells. These studies will pave the way for broader application of immunotherapy in cancer patients.

Thomas Schmitt: Working at a biotechnology company for over 10 years and writing to share the latest technology for over 5 years.