PD1 blockade-based combination therapy has been approved as a first-line treatment for head and neck squamous cell carcinoma (HNSCC). However, the response rate remains relatively low, and patients with HNSCC eventually relapse. Here, we show that the combination treatment of anti-PD1 and cisplatin enriched BMI1⁺ CSCs in HNSCC while inhibiting HNSCC growth. In contrast, the pharmacological and genetic inhibition of BMI1 eliminated BMI1⁺ CSCs and enabled PD1 blockade therapy, resulting in the inhibition of metastatic HNSCC and prevention of HNSCC relapses. BMI1 inhibition strongly induced tumor cell-intrinsic immune responses by recruiting and activating CD8⁺ T cells in addition to eliminating BMI1⁺ CSCs. Mechanistically, BMI1 inhibition induced CD8⁺ T cell-recruiting chemokines by stimulating IRF3-mediated transcription and erasing repressive H2A ubiquitination. Our results suggest that targeting BMI1 may enable immune checkpoint blockade to inhibit metastatic tumor growth and prevent tumor relapse by activating cell-intrinsic immunity, in addition to purging CSCs.

基于 PD1 阻断的联合疗法已被批准作为头颈部鳞状细胞癌 (HNSCC) 的一线治疗。然而，反应率仍然相对较低，HNSCC 患者最终会复发。在这里，我们展示了抗 PD1 和顺铂的联合治疗富集了 HNSCC 中的 BMI1 ⁺ CSC，同时抑制了 HNSCC 的生长。相比之下，BMI1 的药理学和基因抑制消除了 BMI1 ⁺ CSCs 并启用了 PD1 阻断治疗，从而抑制转移性 HNSCC 并预防 HNSCC 复发。BMI1 抑制除了消除 BMI1 ^{+外，还通过募集和激活 CD8 +} T 细胞强烈诱导肿瘤细胞内在免疫反应中央干细胞。从机制上讲，BMI1 抑制通过刺激 IRF3 介导的转录和消除抑制性 H2A 泛素化来诱导 CD8 ⁺ T 细胞募集趋化因子。我们的研究结果表明，除了清除 CSC 之外，靶向 BMI1 还可以通过激活细胞内在免疫来抑制免疫检查点阻断以抑制转移性肿瘤的生长并防止肿瘤复发。