A study published in Nature (DOI: 10.1038/s41586-024-07121-9) reveals that the anti-TIGIT antibody tiragolumab enhances the effectiveness of PD-L1 blockade by modulating myeloid and regulatory T cells. In the phase 2 CITYSCAPE trial, tiragolumab combined with atezolizumab showed improved clinical outcomes compared to atezolizumab alone. The study found that higher baseline levels of intratumoural macrophages and regulatory T cells were associated with better responses to the combination therapy. Serum analysis indicated that macrophage activation was linked to clinical benefits in patients receiving the combination treatment. In mouse models, tiragolumab activated tumour-associated macrophages, monocytes, and dendritic cells through Fcγ receptors, which in turn enhanced anti-tumour CD8+ T cells from an exhausted state to a more memory-like state. These findings suggest that FcγR engagement is important for the efficacy of anti-TIGIT antibodies. The study also showed that the combination of anti-TIGIT and anti-PD-L1 antibodies led to increased expression of antigen-presentation genes and reduced expression of genes associated with exhausted T cells. Additionally, the study found that anti-TIGIT antibodies could modulate CD8+ T cells through macrophages, highlighting the importance of FcγR engagement in the therapeutic effect of anti-TIGIT antibodies. The study concludes that the mechanism of action of anti-TIGIT antibodies involves the activation of myeloid cells and the modulation of T cell responses, which can enhance the effectiveness of PD-L1 blockade.A study published in Nature (DOI: 10.1038/s41586-024-07121-9) reveals that the anti-TIGIT antibody tiragolumab enhances the effectiveness of PD-L1 blockade by modulating myeloid and regulatory T cells. In the phase 2 CITYSCAPE trial, tiragolumab combined with atezolizumab showed improved clinical outcomes compared to atezolizumab alone. The study found that higher baseline levels of intratumoural macrophages and regulatory T cells were associated with better responses to the combination therapy. Serum analysis indicated that macrophage activation was linked to clinical benefits in patients receiving the combination treatment. In mouse models, tiragolumab activated tumour-associated macrophages, monocytes, and dendritic cells through Fcγ receptors, which in turn enhanced anti-tumour CD8+ T cells from an exhausted state to a more memory-like state. These findings suggest that FcγR engagement is important for the efficacy of anti-TIGIT antibodies. The study also showed that the combination of anti-TIGIT and anti-PD-L1 antibodies led to increased expression of antigen-presentation genes and reduced expression of genes associated with exhausted T cells. Additionally, the study found that anti-TIGIT antibodies could modulate CD8+ T cells through macrophages, highlighting the importance of FcγR engagement in the therapeutic effect of anti-TIGIT antibodies. The study concludes that the mechanism of action of anti-TIGIT antibodies involves the activation of myeloid cells and the modulation of T cell responses, which can enhance the effectiveness of PD-L1 blockade.