A recent study published in Genes & Diseases reveals a novel role of XPR1 in promoting ovarian cancer growth by regulating autophagy and MHC-I expression. The research, conducted by scientists from Chongqing Medical University, identifies XPR1 as a critical factor influencing the aggressiveness of ovarian cancer through its interaction with LAMP1 and the PI3K/Akt/mTOR signaling pathway. These findings shed light on new therapeutic targets for ovarian cancer, a malignancy known for its poor prognosis and resistance to immune checkpoint inhibitors.

The study highlights that XPR1 expression is significantly increased in ovarian cancer tissues compared to normal ovarian tissues. This heightened expression correlates with advanced cancer stages, reduced overall survival, and lower progression-free survival. Through CRISPR-Cas9 screening, researchers identified XPR1 as a potential regulator of autophagy. Subsequent experiments confirmed that silencing XPR1 decreased ovarian cancer cell proliferation and metastasis, while overexpression led to the opposite effect, indicating its role in promoting cancer growth.

Further analysis revealed that XPR1 interacts with LAMP1, a key lysosomal-associated membrane protein, and regulates its expression. This interaction modulates autophagy flux, particularly during the early phase of autophagy and to some extent during the lysosomal phase. Silencing XPR1 led to increased lysosome formation and autophagy, while its overexpression suppressed these processes. The study demonstrated that XPR1 regulates autophagy through the PI3K/Akt/mTOR pathway, inhibiting autophagy flux and thereby promoting ovarian cancer cell survival.

In addition to autophagy regulation, the study identified a critical role of XPR1 in immune evasion. MHC-I molecules, crucial for CD8+ T cell recognition and tumor cell killing, were found to be regulated by XPR1 through autophagy. Silencing XPR1, combined with the use of chloroquine, an autophagy inhibitor, significantly enhanced the presence of MHC-I molecules on ovarian cancer cells. This combination treatment reduced tumor growth in mouse models, suggesting that targeting XPR1 alongside autophagy inhibition could improve the effectiveness of immunotherapy in ovarian cancer.

These findings suggest that XPR1 serves as a potential therapeutic target for ovarian cancer, especially in cases resistant to PD-1 and CTLA-4 inhibitors. Targeting XPR1, either through direct silencing or by using autophagy inhibitors, may offer a novel approach to enhance the immune response against ovarian cancer. The study provides a foundation for future research into the use of autophagy modulators in combination with immune checkpoint inhibitors to improve treatment outcomes.

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Reference
Hui Wang, Xiaodong Luo, Bo Yang, Furong Tang, Xingwei Jiang, Hongtao Zhu, Jianguo Hu, XPR1 promotes ovarian cancer growth and regulates MHC-I through autophagy, Genes & Diseases, Volume 12, Issue 5, 2025, 101507, https://doi.org/10.1016/j.gendis.2024.101507

Funding Information:
Kuanren Talents Program and Senior Medical Talents Program of the Second Affiliated Hospital of Chongqing Medical University
Senior Medical Talents Program of Chongqing for Young and Middle-aged
Chongqing Science and Technology Bureau Project CSTB2024TIAD-KPX0038