LC-MS/MS analysis of S100A1-interacting proteins

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but the therapeutic response is highly heterogeneous. A potential mode of resistance is tumor-intrinsic mechanisms leading to an immunosuppressive tumor microenvironment. However, the underlying interactive network remains elusive and the generalizable biomarkers and targeting strategies are still lacking. Here, we uncovered the potential of plasma S100 calcium-binding protein A1 (S100A1) in determining ICB efficacy based on liquid biopsy of patients with lung cancer. Muti-omics and functional studies suggested that tumor-intrinsic S100A1 expression correlates with an immunologically cold TME and resistance to ICB. Mechanistic investigations demonstrated that interfering with tumor-intrinsic S100A1/ubiquitin-specific protease 7/p65/granulocyte-macrophage colony-stimulating factor (GM-CSF) modulatory axis could potentiate an inflamed TME via promoting M1-like macrophage polarization and T cell function. GM-CSF priming was sufficient to enhance ICB response in tumors with high S100A1 expression. These findings defined S100A1 as a potential biomarker and a novel synergistic target for cancer immunotherapy.