Immune checkpoint blockade (ICB) has revolutionized cancer treatment, but the therapeutic response is highly heterogeneous, which highlights the necessity for developing predictive biomarkers and overcoming ICB resistance. Cancer cell-intrinsic features, especially those that can be dynamically monitored via liquid biopsy, represent a broader scope for biomarker development. In addition, a potential mode of ICB resistance is tumor-intrinsic mechanisms leading to an immunosuppressive tumor microenvironment (TME). 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) for determining ICB efficacy via liquid biopsy of patients with lung cancer. Multiomics and functional studies have suggested that tumor-intrinsic S100A1 expression correlated with an immunologically "cold" TME and resistance to ICB in multiple syngeneic murine tumors and tissue samples from patients with lung cancer. Mechanistic investigations demonstrated that interfering with the tumor-intrinsic S100A1/ubiquitin-specific protease 7/p65/granulocyte-macrophage colony-stimulating factor (GM-CSF) modulatory axis could potentiate an inflamed TME by promoting M1-like macrophage polarization and T cell function. GM-CSF priming was sufficient to enhance the ICB response in tumors with high S100A1 expression in preclinical models. These findings define S100A1 as a potential blood-based biomarker and a novel synergistic target for cancer immunotherapy.

© 2025. The Author(s).