Dual blockade of TNFR2 and CD47 reshape tumor immune microenvironment and improve antitumor effects in colorectal cancer.

Colorectal cancer (CRC) is a major cause of cancer deaths, with poor outcomes in advanced stages. CD47, overexpressed in CRC, helps tumors evade immune detection by blocking macrophage phagocytosis, while CD47 blockade has shown limited efficacy in CRC. Our study showed that dual blockade of CD47 and TNFR2 demonstrated synergistic antitumor effects in murine CRC models. Since TNFR2 was highly expressed on Tregs and M-MDSCs, combination therapy targeting both CD47 and TNFR2 was tested, resulting in improved tumor control, prolonged survival, and enhanced immune responses by reducing Tregs and M-MDSCs, further increasing CD8(+) T cell activation and macrophage function. A bispecific antibody fusion protein targeting both CD47 and TNFR2, called ATA47, demonstrated comparable efficacy to the combination therapy. Incorporating ATA47 into an oncolytic adenovirus (AdV-ATA47) also enhanced tumor control and immune activation with minimal systemic effects. AdV-ATA47 demonstrated significant antitumor effects in both murine and human tumor models, supporting its potential as a therapeutic strategy, particularly in combination with approved CRC therapies.