尽管目前针对PD-1 / PD-L1免疫检查点以重新激活疲惫的T细胞的癌症免疫疗法已经取得了令人印象深刻的临床结果，但仅有少部分患者对其产生反应。因此，需要确定新的治疗靶点，以进一步释放T细胞的抗肿瘤潜力并使更多患者受益。花生四糖凝集素-9（Gal-9）最初被识别为导致T细胞死亡的TIM-3配体，在肿瘤微环境（TME）中充当免疫抑制调节器，但其作为治疗靶点的潜力仍然很少为人所知。在这里，我们展示了通过抗体中和Gal-9，并与DNA损伤反应（DDR）必需的激酶Ataxia telangiectasia mutated（ATM）的抑制结合使用，是一种有前途的癌症免疫疗法方式。在同基因小鼠模型中，肿瘤中ATM的基因缺失显著增强了抗Gal-9治疗的效果。在机械上，ATM抑制通过cGAS-STING干扰素β（IFNβ）固有免疫途径，大大提高了多种人和鼠肿瘤细胞中Gal-9的表达和分泌。将Gal-9抑制与目前在临床试验中评估的选择性ATM抑制剂AZD1390结合使用，在多个同基因小鼠模型中显著抑制肿瘤生长并延长其寿命，包括对PD-1 / PD-L1阻滞没有反应的免疫原性差的LLC肺癌，同时伴随着T细胞浸润的增加。这些结果揭示了通过STING / IFNβ信号诱导的Gal-9是介导肿瘤免疫逃逸的重要机制，可用于癌症免疫疗法，并揭示了基于抗Gal-9的新型组合策略，可用于广泛的恶性肿瘤治疗，包括那些对PD-1 / PD-L1阻滞剂具有抵抗力的肿瘤。©作者（S）。

Although current cancer immunotherapies that target PD-1/PD-L1 immune checkpoint to reinvigorate exhausted T cells have achieved impressive clinical outcomes, only a small proportion of patients respond. New therapeutic targets are therefore needed to be identified to further unleash the anti-tumor potential of T cells and benefit more patients. Galectin-9 (Gal-9), initially identified as a ligand for TIM-3 to induce T cell death, acts as an immunosuppressive regulator in the tumor microenvironment (TME) but its potential as a therapeutic target remains largely elusive. Here we show that antibody neutralization of Gal-9, in combination with inhibition of Ataxia telangiectasia mutated (ATM), a kinase essential for DNA damage response (DDR), is a promising modality for cancer immunotherapy. Genetic depletion of ATM in tumors markedly potentiated anti-Gal-9 therapy in a syngeneic mouse model. Mechanistically, ATM inhibition greatly upregulated Gal-9 expression and secretion in a variety of human and murine tumor cells via the cGAS-STING-interferon β (IFNβ) innate immune pathway. Combination of Gal-9 inhibition with AZD1390, a selective ATM inhibitor currently evaluated in clinical trials, significantly suppressed tumor growth and prolonged survival in multiple syngeneic mouse models, including the poorly-immunogenic LLC lung tumors that do not respond to PD-1/PD-L1 blockade, concomitant with increased T cell infiltration. These results reveal Gal-9 induction via STING/IFNβ signaling as an important mechanism mediating tumor immune escape that could be targeted for cancer immunotherapies, and unveil a novel anti-Gal-9-based combination strategy for cancer immunotherapies in a wide variety of malignancies, including those resistant to PD-1/PD-L1 blockade.© The author(s).