干扰素-γ (IFN-γ) 是一种有效的细胞因子，对于免疫治疗的反应至关重要，但系统性递送这种细胞因子的传统方法已受到严重的剂量限制毒性的阻碍。在这里，我们设计了一种益生菌菌株，它可以定位肿瘤并局部释放 IFN-γ。这些产生 IFN-γ 的细菌的单次瘤内注射足以驱动全身肿瘤抗原特异性抗肿瘤免疫，且没有可观察到的毒性。尽管癌细胞利用各种抵抗机制来逃避免疫反应，但细菌来源的 IFN-γ 通过激活细胞毒性 Foxp3-CD4 和 CD8 T 细胞，克服了对程序性细胞死亡 1 (PD-1) 阻断的主要抵抗。此外，通过激活自然杀伤 (NK) 细胞，细菌来源的 IFN-γ 还克服了对 PD-1 阻断的获得性耐药机制，特别是 IFN-γ 信号传导和抗原呈递途径中的功能丧失突变。总的来说，这些结果证明了将产生 IFN-γ 的细菌与 PD-1 阻断相结合作为克服免疫治疗耐药性、局部晚期和转移性疾病的治疗策略的前景。

Interferon-γ (IFN-γ) is a potent cytokine critical for response to immunotherapy, yet conventional methods to systemically deliver this cytokine have been hindered by severe dose-limiting toxicities. Here, we engineered a strain of probiotic bacteria that home to tumors and locally release IFN-γ. A single intratumoral injection of these IFN-γ-producing bacteria was sufficient to drive systemic tumor antigen-specific antitumor immunity, without observable toxicity. Although cancer cells use various resistance mechanisms to evade immune responses, bacteria-derived IFN-γ overcame primary resistance to programmed cell death 1 (PD-1) blockade via activation of cytotoxic Foxp3-CD4+ and CD8+ T cells. Moreover, by activating natural killer (NK) cells, bacteria-derived IFN-γ also overcame acquired resistance mechanisms to PD-1 blockade, specifically loss-of-function mutations in IFN-γ signaling and antigen presentation pathways. Collectively, these results demonstrate the promise of combining IFN-γ-producing bacteria with PD-1 blockade as a therapeutic strategy for overcoming immunotherapy-resistant, locally advanced, and metastatic disease.