Discovery of XPR1 Gene Drives Aggressive Ovarian Cancer

Ovarian cancer is a malignant tumor known for its poor diagnosis and resistance to immune checkpoint inhibitors

Ovarian cancer is a malignant tumor known for its poor diagnosis and resistance to immune checkpoint inhibitors (Shutterstock)/Aljazeera.net


 

A groundbreaking study published in Genes & Diseases reveals that the gene XPR1 plays a key role in increasing ovarian cancer aggressiveness by suppressing autophagy and enabling immune evasion. This finding suggests new therapeutic targets to enhance immunotherapy outcomes.

 Key Findings

  • High XPR1 expression is found in ovarian tumors versus normal tissues and correlates with advanced stage, decreased overall survival (OS), and shorter progression-free survival (PFS) .
  • XPR1 silencing via CRISPR‐Cas9 or RNA interference inhibits proliferation and metastasis of ovarian cancer cells; overexpression has opposite effect .
  • Mechanism: autophagy suppression—XPR1 interacts with lysosomal protein LAMP1 and activates the PI3K/Akt/mTOR pathway, decreasing autophagic flux .
  • Immune evasion—XPR1 reduces MHC-I presence on tumor cells via autophagic degradation, hiding them from CD8+ T cells .
  • Combination therapy in mice—Silencing XPR1 along with chloroquine (autophagy inhibitor) increased MHC-I, boosted T-cell recognition, and slowed tumor growth .

 Updated Insight 

Additional analyses confirm XPR1’s direct interaction with LAMP1, modulating early autophagy and lysosomal function—reinforcing that combined targeting of XPR1 and autophagy can restore MHC‑I expression to enhance T-cell mediated tumor clearance .

Moreover, a recent structural biology study (January 2025) mapped the XPR1–KIDINS220 phosphate‑exporter complex. Targeting this complex disrupts phosphate export, triggering toxic accumulation in cancer cells—offering a dual therapeutic angle by inhibiting both phosphate signaling and immune evasion .

 Therapeutic Implications

  1. XPR1 inhibition + autophagy inhibition (e.g., chloroquine) may reinstate MHC-I surface expression and T-cell killing.
  2. Targeting XPR1–KIDINS220 complex disrupts phosphate homeostasis and enhances tumor cell vulnerability.
  3. Combining checkpoint inhibitors (PD-1/PD-L1 or CTLA-4) with autophagy modulators may improve therapy responsiveness.

 Sources & References

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