Vactosertib enhances radiotherapy efficacy by modulating radiation-induced tumor microenvironment remodeling in breast cancer

Abstract

Background. Radiotherapy (RT) is a standard treatment for breast cancer; however, it can induce unfavorable alterations in the tumor microenvironment (TME), including inflammatory responses, fibrosis, and immune dysregulation, which may compromise therapeutic efficacy and contribute to suboptimal treatment outcomes. This study aimed to investigate whether Vactosertib, a TGF-β receptor I inhibitor, could modulate RT-induced TME changes and improve treatment outcomes.

Materials and methods. A breast tumor-bearing mouse model was established and treated with RT alone or in combination with Vactosertib. Mice received fractionated irradiation (4 Gy/day for 3 days) and oral administration of Vactosertib (2.5 mg/kg for 2 weeks). Tumor progression, gene expression, cytokine profiles, immune cell infiltration, and fibrosis were analyzed using microarray analysis, quantitative PCR, ELISA, and histological assessments.

Results. RT alone reduced tumor volume but induced transcriptional and cytokine changes associated with inflammation and fibrosis within tumor tissues. In contrast, co-treatment with Vactosertib significantly enhanced tumor suppression compared with RT alone. This was accompanied by reduced expression of pro-inflammatory cytokines, decreased collagen deposition, and increased infiltration of CD8⁺ T cells, indicating a shift toward a more favorable anti-tumor immune microenvironment.

Conclusions. These findings suggest that Vactosertib may enhance the therapeutic efficacy of RT by modulating radiation-induced inflammatory and fibrotic changes in the TME, supporting its potential as a rational combination strategy to improve radiotherapy outcomes in breast cancer.