Inflammation can support or restrain cancer progression and the response to therapy. Here, we searched for primary regulators of cancer-inhibitory inflammation through deep profiling of inflammatory tumor microenvironments (TMEs) linked to immune-dependent control in mice. We found that early intratumoral accumulation of interferon gamma (IFN-γ)-producing natural killer (NK) cells induced a profound remodeling of the TME and unleashed cytotoxic T cell (CTL)-mediated tumor eradication. Mechanistically, tumor-derived prostaglandin E2 (PGE2) acted selectively on EP2 and EP4 receptors on NK cells, hampered the TME switch, and enabled immune evasion. Analysis of patient datasets across human cancers revealed distinct inflammatory TME phenotypes resembling those associated with cancer immune control versus escape in mice. This allowed us to generate a gene-expression signature that integrated opposing inflammatory factors and predicted patient survival and response to immune checkpoint blockade. Our findings identify features of the tumor inflammatory milieu associated with immune control of cancer and establish a strategy to predict immunotherapy outcomes.

炎症可以支持或抑制癌症进展和对治疗的反应。在这里，我们通过深入分析与小鼠免疫依赖性控制相关的炎症性肿瘤微环境 (TME)，寻找抑制癌症的炎症的主要调节因子。我们发现，产生干扰素 γ (IFN-γ) 的自然杀伤 (NK) 细胞的早期肿瘤内积累诱导了 TME 的深刻重塑并释放了细胞毒性 T 细胞 (CTL) 介导的肿瘤根除。从机制上讲，肿瘤来源的前列腺素 E2 (PGE2) 选择性地作用于 NK 细胞上的 EP2 和 EP4 受体，阻碍 TME 开关，并实现免疫逃避。对人类癌症患者数据集的分析揭示了不同的炎症 TME 表型，类似于与癌症免疫控制和小鼠逃逸相关的那些。这使我们能够生成一个基因表达特征，该特征整合了相反的炎症因子，并预测了患者的存活率和对免疫检查点阻断的反应。我们的研究结果确定了与癌症免疫控制相关的肿瘤炎症环境的特征，并建立了预测免疫治疗结果的策略。