Enhancing immune cell functions in tumors remains a major challenge in cancer immunotherapy. Hypoxia is a common feature of solid tumors, and cells adapt by upregulating the transcription factor HIF-1α. Here, we defined the transcriptional landscape of mouse tumor-infiltrating natural killer (NK) cells by using single-cell RNA sequencing. Conditional deletion of Hif1a in NK cells resulted in reduced tumor growth, elevated expression of activation markers, effector molecules, and an enriched NF-κB pathway in tumor-infiltrating NK cells. Interleukin-18 (IL-18) from myeloid cells was required for NF-κB activation and the enhanced anti-tumor activity of Hif1a^−/− NK cells. Extended culture with an HIF-1α inhibitor increased human NK cell responses. Low HIF1A expression was associated with high expression of IFNG in human tumor-infiltrating NK cells, and an enriched NK-IL18-IFNG signature in solid tumors correlated with increased overall patient survival. Thus, inhibition of HIF-1α unleashes NK cell anti-tumor activity and could be exploited for cancer therapy.

增强肿瘤中的免疫细胞功能仍然是癌症免疫疗法中的主要挑战。缺氧是实体瘤的常见特征，细胞可通过上调转录因子HIF-1α来适应。在这里，我们通过使用单细胞RNA测序定义了小鼠肿瘤浸润性自然杀伤（NK）细胞的转录态势。NK细胞中Hif1a的条件缺失导致肿瘤生长减少，激活标记物，效应分子的表达升高以及肿瘤浸润NK细胞中丰富的NF-κB途径。NF-κB活化和Hif1a ^-/- NK细胞增强的抗肿瘤活性需要髓样细胞的白介素18（IL-18）。用HIF-1α抑制剂进行的扩展培养可增强人类NK细胞的反应。低HIF1A表达与人肿瘤浸润性NK细胞中IFNG的高表达有关，实体瘤中丰富的NK - IL18-IFNG签名与患者总体生存期增加相关。因此，抑制HIF-1α可释放NK细胞的抗肿瘤活性，可用于癌症治疗。