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Inactivating LATS2 variation drives tumor progression and resistance to anti-PD-1 therapy in intrahepatic

Ye Xu1,2, Kai-Xuan Liu1,2, Xin-Yu Wang1,2

  • 1Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.

Clinical and Molecular Hepatology
|March 18, 2026
PubMed
Abstract

Insights

Inactivating LATS2 variations in intrahepatic cholangiocarcinoma (ICC) correlate with poor survival and immune evasion. These LATS2 alterations promote tumor progression and resistance to anti-PD-1 therapy, offering a potential biomarker for precision treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunotherapy

Background:

  • Recurrence significantly limits long-term survival in intrahepatic cholangiocarcinoma (ICC) patients.
  • Molecular drivers and therapeutic targets for ICC remain largely undefined, necessitating further research.

Purpose of the Study:

  • To investigate the role of LATS2 gene variations in ICC.
  • To determine the impact of LATS2 alterations on patient survival and response to anti-PD-1 therapy.
  • To elucidate the underlying mechanisms of LATS2 in ICC progression and immune evasion.

Main Methods:

  • Targeted and Sanger sequencing, and quantitative PCR were used to analyze LATS2 in 400 ICC samples.
  • Kaplan-Meier survival analysis assessed the impact of LATS2 mutations and copy number loss on patient outcomes.
  • Functional studies explored LATS2's role in the Hippo signaling pathway, immune evasion, and anti-PD-1 therapy resistance.

Main Results:

  • LATS2 somatic mutations (3%) and copy number loss (34%) were identified in ICC, both correlating with decreased LATS2 expression, increased recurrence, and poorer survival.
  • LATS2 inactivation suppressed the Hippo pathway, leading to YAP activation, PD-L1 upregulation, and CCL2 secretion.
  • Tumor immune evasion was promoted through suppressed CD8+ T cell infiltration and increased M2-like macrophage recruitment, contributing to anti-PD-1 resistance.

Conclusions:

  • LATS2-inactivating variations are clinically associated with ICC progression and poor survival.
  • LATS2 alterations represent a potential biomarker for guiding precision therapy in ICC patients.
  • Understanding LATS2's mechanistic role offers insights into overcoming immune evasion and therapeutic resistance in ICC.
Keywords:
ImmunotherapyIntrahepatic cholangiocarcinomaLATS2PD-L1Recurrence

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