Treatment for a number of cancer types has changed significantly with the development of cancer immunotherapy. However, tumors can employ multiple mechanisms to suppress the immune system and evade immune-mediated elimination. This has encouraged researchers to explore therapies that can target multiple immunosuppressive pathways.
One promising approach is Retlirafusp alfa, a bifunctional fusion protein designed to simultaneously target two important immunosuppressive pathways: PD-L1 and transforming growth factor-beta (TGF-β).
Gastric cancer and gastroesophageal junction cancer
Gastric cancer and gastroesophageal junction cancer (GC/GEJC) are two aggressive and closely related diseases that can be challenging to treat, particularly when diagnosed at an advanced stage.
Gastric cancer develops in the stomach, while gastroesophageal junction cancer originates in the area where the esophagus meets the stomach. Although the exact causes are not fully understood, a combination of genetic, environmental, and lifestyle factors may contribute to their development.
In patients with unresectable or metastatic disease, the prognosis remains poor. Early-stage gastric and GEJ cancers may cause few or nonspecific symptoms. When symptoms occur, they can include loss of appetite, dyspepsia, weight loss, abdominal pain, and dysphagia, particularly when the tumor is located at the gastroesophageal junction or proximal stomach.
Because of this often subtle or insidious presentation, a significant proportion of patients are diagnosed with unresectable or metastatic disease.
The challenge is not only the advanced nature of these cancers but also the complex tumor microenvironment that can suppress the body’s immune response. Pathways involving PD-L1 and TGF-β can contribute to this immune suppression, making them important targets for the development of new treatment strategies. This provides the rationale for investigating therapies such as Retlirafusp alfa, which is designed to target both pathways simultaneously.
How does Retlirafusp alfa work?
Retlirafusp alfa is a bifunctional antibody fusion protein that combines a PD-L1-targeting antibody with a truncated form of the extracellular domain of TGF-β receptor II (TGF-βRII). It is being developed for the treatment of solid malignant tumors.
The mechanism of action of Retlirafusp alfa can be understood as a two-pronged strategy.
First, its anti-PD-L1 component binds to PD-L1 and blocks PD-L1-mediated immune checkpoint signaling. This may help restore the activity of immune cells, including cytotoxic T lymphocytes and natural killer cells, against tumor cells.
Second, the TGF-β receptor component is designed to capture and neutralize TGF-β. Reducing TGF-β signaling may help counter the immunosuppressive tumor microenvironment and support anti-tumor immune activity.
By targeting these two complementary mechanisms in a single molecule, Retlirafusp alfa is designed to address multiple aspects of tumor-mediated immune suppression.
Retlirafusp Alfa and Gastric Cancer
The dual-targeting mechanism of Retlirafusp alfa has particular relevance to gastric and gastroesophageal junction cancers, where there remains a need for effective treatment options for patients with advanced disease.
One of the most significant developments for Retlirafusp alfa came in January 2026, when China’s National Medical Products Administration approved the drug for a specific first-line treatment setting.
The approval covers Retlirafusp alfa in combination with fluorouracil- and platinum-based chemotherapy for patients with locally advanced unresectable, recurrent, or metastatic gastric cancer or gastroesophageal junction adenocarcinoma whose tumors are PD-L1 positive, defined as a combined positive score (CPS) of at least 1 using a validated test.
This approval represents an important milestone in the development of the drug , moving it from clinical investigation into clinical use for an eligible patient population in China.
Potential Benefits of Retlirafusp Alfa
The potential advantages are primarily associated with its ability to target two important immunosuppressive pathways simultaneously.
Potential benefits include:
- Dual inhibition of PD-L1 and TGF-β pathways
- Potential enhancement of anti-tumor immune responses
- Potential modulation of the tumor microenvironment
- Potential use in combination with established cancer treatments
- Ongoing investigation across multiple solid tumors
However, the potential benefits of the drug may vary depending on the cancer type, disease stage, biomarker status, treatment regimen, and individual patient characteristics.
Conclusion
Retlirafusp alfa is a novel bifunctional cancer immunotherapy designed to target two important immune-suppressive pathways: PD-L1 and TGF-β.
Its dual mechanism distinguishes it from conventional single-target checkpoint inhibitors by addressing two complementary pathways involved in tumor immune suppression. This approach is particularly relevant in the context of advanced gastric and gastroesophageal junction cancers, where treatment options remain an important area of clinical research.
