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

While radiotherapy (RT) is a cornerstone treatment for breast cancer, it can paradoxically trigger detrimental changes within the tumor microenvironment (TME). These alterations include exacerbated inflammatory responses, increased fibrosis, and immune dysregulation, which collectively diminish therapeutic effectiveness and contribute to suboptimal patient outcomes. Targeting the TME, rather than solely tumor cells, represents a promising strategy to overcome these limitations. This study investigates Vactosertib, a TGF-β receptor I inhibitor, as a potential agent to counteract RT-induced TME remodeling and improve treatment success.

Researchers established a breast tumor-bearing mouse model to evaluate Vactosertib's impact on radiotherapy. Mice were divided into groups receiving either fractionated irradiation alone (4 Gy/day for 3 days) or in combination with oral administration of Vactosertib 2.5 mg/kg daily for 2 weeks. Primary endpoints included tumor progression, assessed by tumor volume measurements. Comprehensive analyses of the TME involved microarray analysis and quantitative RT-PCR for gene expression, ELISA for cytokine profiles, and histological assessments to quantify immune cell infiltration and collagen deposition (fibrosis).

Radiotherapy alone effectively reduced tumor volume, but this benefit was accompanied by undesirable transcriptional and cytokine changes within the tumor tissues, indicative of increased inflammation and fibrosis. In stark contrast, the combination treatment with Vactosertib significantly enhanced tumor suppression when compared to RT alone. This improved anti-tumor effect was directly linked to a more favorable shift in the TME. Specifically, the combination therapy led to reduced expression of pro-inflammatory cytokines and a notable decrease in collagen deposition, a marker of fibrosis. Furthermore, the study observed an increased infiltration of CD8+ T cells, suggesting a robust enhancement of anti-tumor immune responses. > The combination of Vactosertib with radiotherapy significantly enhanced tumor suppression and shifted the tumor microenvironment towards an anti-tumor immune profile.