抑制自噬相关蛋白 7 增强了微卫星不稳定结直肠癌的抗肿瘤免疫反应，并提高了免疫检查点阻断的疗效。

BACKGROUND: The efficacy of anti-PD-1 therapy is primarily hindered by the limited T-cell immune response rate and immune evasion capacity of tumor cells. Autophagy-related protein 7 (ATG7) plays an important role in autophagy and it has been linked to cancer. However, the role of ATG7 in the effect of immune checkpoint blockade (ICB) treatment on high microsatellite instability (MSI-H)/mismatch repair deficiency (dMMR) CRC is still poorly understood. METHODS: In this study, patients from the cancer genome altas (TCGA) COAD/READ cohorts were used to investigate the biological mechanism driving ATG7 development. Several assays were conducted including the colony formation, cell viability, qRT-PCR, western blot, immunofluorescence, flow cytometry, ELISA, immunohistochemistry staining and in vivo tumorigenicity tests. RESULTS: We found that ATG7 plays a crucial role in MSI-H CRC. Its knockdown decreased tumor growth and caused an infiltration of CD8 T effector cells in vivo. ATG7 inhibition restored surface major histocompatibility complex I (MHC-I) levels, causing improved antigen presentation and anti-tumor T cell response by activating reactive oxygen species (ROS)/NF-κB pathway. Meanwhile, ATG7 inhibition also suppressed cholesterol accumulation and augmentation of anti-tumor immune responses. Combining ATG7 inhibition and statins improved the therapeutic benefit of anti-PD-1 in MSI-H CRC. Importantly, CRC patients with high expression of both ATG7 and recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) experienced worse prognosis compared to those with low ATG7 and HMGCR expression. CONCLUSIONS: Inhibition of ATG7 leads to upregulation of MHC-I expression, augments immune response and suppresses cholesterol accumulation. These findings demonstrate that ATG7 inhibition has therapeutic potential and application of statins can increase the sensitivity to immune checkpoint inhibitors.

背景：抗 PD-1 治疗的疗效主要受到肿瘤细胞有限的 T 细胞免疫反应率和免疫逃逸能力的限制。自噬相关蛋白 7（ATG7）在自噬中发挥重要作用，并且与癌症有关。然而，ATG7 在免疫检查点阻断（ICB）治疗对高微卫星不稳定性（MSI-H）/错配修复缺陷（dMMR）CRC 疗效中的作用仍知之甚少。

方法：本研究利用癌症基因组图谱（TCGA）COAD/READ 队列中的患者来研究驱动 ATG7 发展的生物学机制。进行了几种检测，包括集落形成、细胞活力、qRT-PCR、western blot、免疫荧光、流式细胞术、ELISA、免疫组化染色和体内肿瘤生成试验。

结果：我们发现 ATG7 在 MSI-H CRC 中发挥关键作用。其敲低减少了肿瘤生长，并在体内引起 CD8 T 效应细胞浸润。ATG7 抑制恢复了表面主要组织相容性复合体 I（MHC-I）水平，通过激活活性氧（ROS）/NF-κB 通路，改善抗原呈递和抗肿瘤 T 细胞反应。同时，ATG7 抑制还抑制了胆固醇积累和抗肿瘤免疫反应的增强。联合 ATG7 抑制和他汀类药物改善了 MSI-H CRC 中抗 PD-1 的治疗效果。重要的是，CRC 患者中 ATG7 和重组 3-羟基-3-甲基戊二酰基辅酶 A 还原酶（HMGCR）的表达均较高者的预后较 ATG7 和 HMGCR 表达均较低者差。

结论：抑制 ATG7 导致 MHC-I 表达上调，增强免疫反应并抑制胆固醇积累。这些发现表明 ATG7 抑制具有治疗潜力，他汀类药物的应用可以增加对免疫检查点抑制剂的敏感性。