主要组织相容性复合物 I 类 (MHC-I) 的抗原呈递对于 T 细胞介导的杀伤至关重要，并且异常的表面 MHC-I 表达与免疫逃避密切相关。为了解决 MHC-I 下调问题，我们进行了高通量流式细胞术筛选，确定博来霉素 (BLM) 是细胞表面 MHC-I 表达的有效诱导剂。 BLM 诱导的 MHC-I 增强使肿瘤细胞在共培养测定中对 T 细胞更敏感，并增强过继性细胞转移小鼠模型中的抗肿瘤反应。从机制上讲，BLM 重塑肿瘤免疫微环境，以 ATM/ATR-NF-κB 依赖性方式诱导 MHC-I 表达。此外，BLM 改进了 T 细胞依赖性免疫治疗方法，包括双特异性抗体治疗、免疫检查点治疗 (ICT) 和自体肿瘤浸润淋巴细胞 (TIL) 治疗。重要的是，在小鼠模型中进行低剂量 BLM 治疗放大了免疫疗法的抗肿瘤效果，且没有检测到肺部毒性。总之，我们的研究结果将 BLM 重新定位为 MHC-I 的潜在诱导剂，增强其表达以提高基于 T 细胞的免疫疗法的功效。

Antigen presentation by Major Histocompatibility Complex Class I (MHC-I) is crucial for T-cell-mediated killing, and aberrant surface MHC-I expression is tightly associated with immune evasion. To address MHC-I downregulation, we conducted a high-throughput flow cytometry screen, identifying bleomycin (BLM) as a potent inducer of cell surface MHC-I expression. BLM-induced MHC-I augmentation renders tumor cells more susceptible to T cells in co-culture assays and enhances anti-tumor responses in an adoptive cellular transfer mouse model. Mechanistically, BLM remodels the tumor immune microenvironment, inducing MHC-I expression in an ATM/ATR-NF-κB-dependent manner. Furthermore, BLM improves T-cell-dependent immunotherapeutic approaches, including bispecific antibodies therapy, immune checkpoint therapy (ICT), and autologous tumor-infiltrating lymphocytes (TILs) therapy. Importantly, low-dose BLM treatment in mouse models amplified the anti-tumor effect of immunotherapy without detectable pulmonary toxicity. In summary, our findings repurpose BLM as a potential inducer of MHC-I, enhancing its expression to improve the efficacy of T-cell-based immunotherapy.