TAE226将免疫冷的头颈部肿瘤重编程为免疫热，增强免疫治疗疗效

Introduction: Current treatment strategies in advanced/recurrent LSCC include chemotherapy, radiation therapy, and immune checkpoint inhibitors (ICI). ICI treatment is associated with durable benefit in about 20% of patients with advanced/incurable platinum-resistant LSCC. There is a clear need to develop strategies to reprogram the tumor microenvironment (TME) from immune-cold to immune-hot to enhance T-cell infiltration and activation that correlate with ICI treatment response. We investigated the therapeutic potential of Focal Adhesion Kinase (FAK) inhibition using a tyrosine kinase inhibitor, TAE226, alone and in combination with anti-PD-1 immune checkpoint blockade, to reprogram the TME and enhance immunotherapeutic responsiveness in a model of platinum-resistant LSCC. Methods: LSCC cell lines (SQ20B, SCC17A) were used to assess the inhibitory response to FAK inhibitors using the CCK-8 assay. RNA-seq was performed to evaluate global transcriptional changes and pathway enrichment. Syngeneic MOC2 mouse models were used to assess the therapeutic efficacy of TAE226 in combination with anti-PD-1 therapy. Post euthanization, the xenografts were processed for isolating single cells and performing single-cell RNA sequencing. Results: TAE226 significantly reduced LSCC cell proliferation, viability, and wound-healing capacity, indicating potent anti-tumor activity. Bulk RNA-seq and pathway enrichment analyses revealed robust upregulation of interferon and cytokine signaling pathways, consistent with an immune-stimulatory phenotype, while downregulating proliferative and metabolic programs. This dual modulation suggests that TAE226 exerts both tumor-intrinsic anti-proliferative and tumor-extrinsic immune-activating effects. In the MOC2 syngeneic model, the combination of TAE226 and anti-PD-1 produced a synergistic response, resulting in markedly enhanced antitumor signaling and significantly greater tumor regression compared to either monotherapy. Single-cell RNA-seq further demonstrated that TAE226 treatment induced profound TME remodeling, characterized by expansion of cytotoxic CD8⁺ T cells, dendritic cells, and activated macrophages, and depletion of proliferative epithelial and fibroblast-rich stromal clusters. Hallmark pathway analyses highlighted activation of interferon-alpha/gamma, IL2-STAT5, TNFA-NFκB, and complement signaling-consistent with broad activation of innate and adaptive immune programs. Conclusion: These findings indicate that TAE226 disrupts FAK-mediated adhesion and cytoskeletal signaling, converting the TME from immune-cold to immune-hot and enhancing responsiveness to immune checkpoint blockade and offering a promising therapeutic strategy for platinum-resistant laryngeal cancer.