C5aR1 Receptor: Potential target for cutaneous Squamous Cell Carcinoma

Updated‍ June‍ 07,2025

The C5aR1 receptor,a component of ⁢the complement system,may represent a promising therapeutic target for cutaneous squamous cell carcinoma (cSCC),according to a new study in the American Journal of Pathology. Researchers found that elevated expression of ⁢C5aR1 in tumor cells and fibroblasts‌ is associated with increased risk of metastasis and ⁤reduced survival⁤ rates in patients with‍ this common skin⁣ cancer.

Cutaneous squamous cell carcinoma ⁣is the most frequently occurring metastatic skin cancer, and its incidence is on the rise. Approximately 3% to 5% of‍ primary cSCC cases metastasize, leading to poor survival outcomes. A prior study​ indicated that patients with metastatic cSCC have ⁢a five-year survival rate of only 37.2%.

The study focused on C5a due to its presence in cSCC and its role as a vasodilator and chemotactic factor. It binds to the C5aR1 receptor,⁣ influencing vascular permeability and ‌cell ⁣degranulation. Prior research has linked C5aR1 upregulation to poor survival in other cancers, such as non-small cell lung cancer and gastric cancer.

Dr. Veli-Matti Kähäri, lead investigator from the University of ⁣turku and⁢ Turku University Hospital in Finland, emphasized the urgent need for predictive biomarkers and new therapeutic targets for metastatic cSCC. The ​research team assessed C5aR1 levels using in ‍vitro and in vivo models, including patient-derived ⁣tumor samples.

Dr. Lauri Heiskanen, the study’s first author, noted that fibroblasts in the tumor microenvironment induce C5aR1 expression in cSCC cells. Exposure to C5a ‌further ​enhanced the invasiveness of ‍these cells.High C5aR1 expression ⁣in patient ⁣samples correlated with increased⁣ metastasis risk ‍and decreased survival.

According‌ to Drs. Pilvi Riihilä and liisa Nissinen, also from the ⁣University of⁣ Turku, the study highlights ⁣the critical role of the tumor microenvironment, notably fibroblasts, in cSCC progression through C5aR1. This underscores the importance of interactions between tumor cells and stromal cells in ⁣cancer development.

Currently, three immune-oncologic antibody treatments targeting the programmed cell death protein 1/programmed death ligand 1 pathway are ⁤approved for advanced cSCC. The study ​suggests that targeting the C5a-C5aR1 axis could complement these existing ‍therapies. Several anti-C5a antibodies and a small-molecule inhibitor of C5aR1 ‍are already approved for inflammatory diseases and might ‌potentially be viable​ options for advanced cSCC and other cancers. Furthermore, assessing C5aR1 levels could help clinicians better assess individual patient risk.

“We observed that fibroblasts in the tumor microenvironment induced C5aR1 ‌expression in cSCC cells,” said Dr. Lauri Heiskanen.

What’s next

Future research will likely focus on clinical trials to evaluate the efficacy of C5aR1 inhibitors in combination with existing treatments for cutaneous squamous cell carcinoma, potentially improving outcomes for patients ​with ​metastatic‌ disease.