The study investigates the mechanism by which the anti-TIGIT antibody tiragolumab, combined with atezolizumab (an anti-PD-L1 antibody), improves outcomes in patients with non-small cell lung cancer (NSCLC). Key findings include: 1. **Clinical Biomarker Analysis**: High baseline levels of intratumoural macrophages and regulatory T cells (Treg) are associated with better outcomes in patients treated with tiragolumab plus atezolizumab compared to atezolizumab alone. Serum analysis revealed that macrophage activation is linked to clinical benefit in patients receiving the combination treatment. 2. **Preclinical Studies**: In mouse models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes, and dendritic cells through Fcγ receptors (FcγR), driving anti-tumour CD8+ T cells from an exhausted state to a more memory-like state. 3. **FcγR Engagement**: The study suggests that FcγR engagement is crucial for the efficacy of anti-TIGIT antibodies. In preclinical models, FcγR engagement was required for the therapeutic activity of anti-TIGIT monoclonal antibodies, and it synergized with anti-PD-L1 antibodies to enhance tumour microenvironment remodeling. 4. **Macrophages and Treg Cells**: Macrophages and Treg cells, typically suppressive in the tumour microenvironment, were found to potentiate the activity of tiragolumab. Depletion of macrophages with anti-CSF-1R antibodies reversed the beneficial effects of tiragolumab, indicating that macrophages play a key role in mediating the anti-tumour response. 5. **Clinical Data**: The combination treatment with tiragolumab and atezolizumab demonstrated superior clinical benefit compared to atezolizumab alone, with improved objective response rates, progression-free survival, and overall survival in the intent-to-treat population. These findings highlight the importance of FcγR engagement in the mechanism of action of anti-TIGIT antibodies and suggest that this aspect should be considered in the development of anti-TIGIT therapies.The study investigates the mechanism by which the anti-TIGIT antibody tiragolumab, combined with atezolizumab (an anti-PD-L1 antibody), improves outcomes in patients with non-small cell lung cancer (NSCLC). Key findings include: 1. **Clinical Biomarker Analysis**: High baseline levels of intratumoural macrophages and regulatory T cells (Treg) are associated with better outcomes in patients treated with tiragolumab plus atezolizumab compared to atezolizumab alone. Serum analysis revealed that macrophage activation is linked to clinical benefit in patients receiving the combination treatment. 2. **Preclinical Studies**: In mouse models, tiragolumab surrogate antibodies inflamed tumour-associated macrophages, monocytes, and dendritic cells through Fcγ receptors (FcγR), driving anti-tumour CD8+ T cells from an exhausted state to a more memory-like state. 3. **FcγR Engagement**: The study suggests that FcγR engagement is crucial for the efficacy of anti-TIGIT antibodies. In preclinical models, FcγR engagement was required for the therapeutic activity of anti-TIGIT monoclonal antibodies, and it synergized with anti-PD-L1 antibodies to enhance tumour microenvironment remodeling. 4. **Macrophages and Treg Cells**: Macrophages and Treg cells, typically suppressive in the tumour microenvironment, were found to potentiate the activity of tiragolumab. Depletion of macrophages with anti-CSF-1R antibodies reversed the beneficial effects of tiragolumab, indicating that macrophages play a key role in mediating the anti-tumour response. 5. **Clinical Data**: The combination treatment with tiragolumab and atezolizumab demonstrated superior clinical benefit compared to atezolizumab alone, with improved objective response rates, progression-free survival, and overall survival in the intent-to-treat population. These findings highlight the importance of FcγR engagement in the mechanism of action of anti-TIGIT antibodies and suggest that this aspect should be considered in the development of anti-TIGIT therapies.