T cells within the tumor microenvironment frequently exhibit dysfunctional characteristics that compromise their ability to elicit both innate and therapeutic-induced immune responses. Regulators of immune dysfunction represent therapeutic targets to activate anti-tumor immunity. In this study, we identified semaphorin 3G (SEMA3G) as a key regulator of immune responses in cancer. SEMA3G was widely upregulated in diverse human cancers, and its expression was positively correlated with tumor progression. SEMA3G acted as a ligand that inhibited the activation and functionality of T cells. A comprehensive receptor screening approach demonstrated that SEMA3G exhibited a significantly stronger affinity for neuropilin NRP1 compared to NRP2. Furthermore, SEMA3G primarily impeded T-cell functions via NRP1. Disruption of SEMA3G using CRISPR/Cas9 technology or blockade with a neutralizing antibody effectively restored the cytotoxicity of CD8+ T cells and inhibited the growth of tumors in vivo. This research underscores the role of SEMA3G in T-cell dysfunction within tumors and proposes a targeting SEMA3G as a cancer immunotherapeutic strategy.

中文翻译：

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SEMA3G-NRP1 信号转导作为免疫检查点发挥作用，通过削弱 T 细胞细胞毒性实现肿瘤免疫逃逸


肿瘤微环境中的 T 细胞经常表现出功能失调的特征，这损害了它们引发先天性和治疗性诱导的免疫反应的能力。免疫功能障碍调节因子是激活抗肿瘤免疫的治疗靶点。在这项研究中，我们确定信号素 3G （SEMA3G） 是癌症免疫反应的关键调节因子。SEMA3G 在多种人类癌症中广泛上调，其表达与肿瘤进展呈正相关。SEMA3G 作为配体，抑制 T 细胞的活化和功能。全面的受体筛选方法表明，与 NRP2 相比，SEMA3G 对神经纤毛蛋白 NRP1 的亲和力明显增强。此外，SEMA3G 主要通过 NRP1 阻碍 T 细胞功能。使用 CRISPR/Cas9 技术破坏 SEMA3G 或用中和抗体封闭可有效恢复 CD8+ T 细胞的细胞毒性并抑制体内肿瘤的生长。这项研究强调了 SEMA3G 在肿瘤内 T 细胞功能障碍中的作用，并提出了一种靶向 SEMA3G 作为癌症免疫治疗策略。