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<p>Cancer cells frequently exhibit MHC-I deficiency, impairing immune-mediated cytotoxicity even in the presence of PD-1 checkpoint inhibition. To date, no clinically approved therapies exist that can upregulate MHC-I expression to boost immune responses against cancer cells. Emerging evidence has shown that autophagy plays a role in MHC-I molecule degradation, contributing to reduced recognition of cancer cells by CD8<sup>+</sup> T cells. We previously report that fangchinoline, a bisbenzylisoquinoline alkaloid derived from Chinese herb, is a novel autophagy inhibitor with an adjuvant of chemotherapy against lung cancer. In this study we investigated the modulatory effects of PD-1 blockade combined with fangchinoline on CD8<sup>+</sup> T cells within the tumor microenvironment of lung cancer. We showed an inverse correlation between elevated autophagic activity and decreased MHC-I surface expression—a phenomenon often associated with poor clinical efficacies—in various human lung cancer cell lines (NCI-H1299, NCI-H1975, A549, NCI-H1650 and NCI-H446) compared with normal bronchial epithelial cells lung cancer. Knockdown of ATG4 and ATG5 resulted in increased MHC-I expression and enhanced tumor antigen presentation in NCI-H1975, NCI-H1299 and A549 cells. As autophagy receptors were crucial for transporting proteins to autophagosomes for degradation, we sequentially silenced various autophagy receptors and found that NDP52 knockdown specifically restored MHC-I expression, suggesting that NDP52-mediated autophagy might contribute to MHC-I degradation, and autophagy inhibition might enhance immune-mediated cancer cell death. We showed that pretreatment of LLC-OVA cells with the autophagy inhibitor fangchinoline (1.25, 2.5, 5 μM) followed by coculture with CD8<sup>+</sup> T cells, dose-dependently enhanced immune killing. In both in vitro and in vivo experiments, we showed that fangchinoline combined with anti-PD-1 therapy significantly increased CD8<sup>+</sup> T cell–mediated cytotoxicity. In conclusion, this study highlights NDP52 as a key autophagy receptor involved in MHC-I degradation and provides a new insight into tumor immune evasion. Combining autophagy inhibition with immunotherapy may be a promising therapeutic strategy for anticancer immunity enhancement.</p>

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Fangchinoline-mediated autophagy inhibition amplifies antigen presentation and PD-1 blockade efficacy in lung cancer

  • 期刊论文

  • 发表日期：

    2025年4月23日

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  • Yue Song,
  • Yu-xiao Jiang,
  • Jie-ying Guan,
  • Jun-bo Jiang,
  • Man-si Xu,
  • Xue-ying Zhong,
  • Li-na He,
  • Zhen-yang Ren,
  • Yuan Liao,
  • Fang Liu,
  • Yan-jun Jiang,
  • Shan Hu,
  • Wei Guo,
  • Ting-xiu Zhao,
  • Xiao-yi Liu,
  • Jiang-yong Gu,
  • Ya-fei Shi,
  • Huan-huan Luo,
  • Kun Wang,
  • Jian-yong Xiao

摘要

Cancer cells frequently exhibit MHC-I deficiency, impairing immune-mediated cytotoxicity even in the presence of PD-1 checkpoint inhibition. To date, no clinically approved therapies exist that can upregulate MHC-I expression to boost immune responses against cancer cells. Emerging evidence has shown that autophagy plays a role in MHC-I molecule degradation, contributing to reduced recognition of cancer cells by CD8+ T cells. We previously report that fangchinoline, a bisbenzylisoquinoline alkaloid derived from Chinese herb, is a novel autophagy inhibitor with an adjuvant of chemotherapy against lung cancer. In this study we investigated the modulatory effects of PD-1 blockade combined with fangchinoline on CD8+ T cells within the tumor microenvironment of lung cancer. We showed an inverse correlation between elevated autophagic activity and decreased MHC-I surface expression—a phenomenon often associated with poor clinical efficacies—in various human lung cancer cell lines (NCI-H1299, NCI-H1975, A549, NCI-H1650 and NCI-H446) compared with normal bronchial epithelial cells lung cancer. Knockdown of ATG4 and ATG5 resulted in increased MHC-I expression and enhanced tumor antigen presentation in NCI-H1975, NCI-H1299 and A549 cells. As autophagy receptors were crucial for transporting proteins to autophagosomes for degradation, we sequentially silenced various autophagy receptors and found that NDP52 knockdown specifically restored MHC-I expression, suggesting that NDP52-mediated autophagy might contribute to MHC-I degradation, and autophagy inhibition might enhance immune-mediated cancer cell death. We showed that pretreatment of LLC-OVA cells with the autophagy inhibitor fangchinoline (1.25, 2.5, 5 μM) followed by coculture with CD8+ T cells, dose-dependently enhanced immune killing. In both in vitro and in vivo experiments, we showed that fangchinoline combined with anti-PD-1 therapy significantly increased CD8+ T cell–mediated cytotoxicity. In conclusion, this study highlights NDP52 as a key autophagy receptor involved in MHC-I degradation and provides a new insight into tumor immune evasion. Combining autophagy inhibition with immunotherapy may be a promising therapeutic strategy for anticancer immunity enhancement.