RESUMEN
Smad ubiquitylation regulatory factor 1 (Smurf1) is an important homologous member of E6-AP C-terminus type E3 ubiquitin ligase. Initially, Smurf1 was reportedly involved in the negative regulation of the bone morphogenesis protein (BMP) pathway. After further research, several studies have confirmed that Smurf1 is widely involved in various biological processes, such as bone homeostasis regulation, cell migration, apoptosis, and planar cell polarity. At the same time, recent studies have provided a deeper understanding of the regulatory mechanisms of Smurf1's expression, activity, and substrate selectivity. In our review, a brief summary of recent important biological functions and regulatory mechanisms of E3 ubiquitin ligase Smurf1 is proposed.
RESUMEN
Background: For programmed cell death protein 1/programmed death-ligand 1 (PD-L1)-positive triple-negative breast cancer (TNBC), the addition of immune checkpoint inhibitors (ICIs) to chemotherapy has been shown to increase the objective response rate (ORR) by only 13.4-16.3%. Thus, examining converting tumor immunogenicity and targeting novel pathways may be needed to improve response to immunotherapy. B7-H4 is an emerging target for breast cancer immunotherapy. However, the antitumor effect of B7-H4 is unstable during cell generation and further research is necessary to strengthen the antitumor efficacy of B7-H4. Methods: To explore the potential of B7-H4-targeted immunotherapy of breast cancer, current study generated four monoclonal antibodies (mAbs) against B7-H4 through immunization of mice followed by phage display technology. T cell-engaged bispecific antibodies and immunotoxins were created based on these mAbs. To evaluate the anti-tumor activity of B7-H4-targeting bispecific antibody and immunotoxin, the anti-tumor efficacy test in vitro and in mice models in vivo were performed. Moreover, to boost the efficacy, oncolytic virus herpes simplex virus type 2 (HSV-2) was combined with the bispecific antibody and tested in mice models. Results: Rigorous in vitro cytotoxicity assay showed that both B7-H4 bispecific antibodies and immunotoxins were toxic to B7-H4 positive cells, with the former being more potent. However, in vivo studies showed that immunotoxin was slightly more effective in suppressing tumor growth. Further, bispecific antibody combined with oncolytic virus HSV-2 revealed a synergistic effect in suppressing tumor growth without causing obvious adverse effects. Conclusions: Collectively, our findings uncover a novel strategy of combining oncolytic virus HSV-2 with bispecific antibody reinforce antitumor immune response, which warranted further translational investigation.
