Radiotherapy disrupts ferroptosis tolerance by reducing DNMT1 levels and uncouples STING silencing in LKB1-deficient...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Liver kinase B1 (LKB1) deficiency is a key driver of primary resistance to immune checkpoint inhibitors (ICIs) in non-small cell lung cancer.
• The precise mechanisms underlying LKB1 deficiency-mediated ICI resistance remain incompletely understood.

Purpose of the Study:

• To elucidate the mechanisms by which LKB1 deficiency confers resistance to ICIs in lung cancer.
• To identify potential therapeutic strategies to overcome ICI resistance in LKB1-deficient lung tumors.

Main Methods:

• Single-cell RNA sequencing analysis of a Kras^G12D/+-driven mouse model with conditional Lkb1 knockout.
• In vitro and in vivo experiments assessing ferroptosis susceptibility and immune microenvironment activation.
• Analysis of clinical cohorts to correlate LKB1 status with ferroptosis resistance and immunotherapy outcomes.

Main Results:

• LKB1-deficient tumors exhibit dysregulated ferroptosis pathways and elevated ferroptosis resistance scores, correlating with immunotherapy failure.
• LKB1 deficiency impairs cellular susceptibility to ferroptosis, which can be reversed by radiotherapy via DNMT1-dependent OSGIN1 downregulation.
• Radiotherapy reactivates STING pathway expression, enhancing the immune microenvironment in LKB1-deficient lung tumors.
• Combination of radiotherapy and anti-PD-1 antibodies demonstrates significant tumor suppression in a murine model through ferroptosis-dependent mechanisms.

Conclusions:

• LKB1 deficiency promotes ferroptosis resistance in lung cancer, contributing to ICI resistance.
• Radiotherapy can overcome LKB1-deficiency-induced ferroptosis resistance and ICI resistance by modulating the DNMT1-OSGIN1 axis and activating STING signaling.
• The combination of radiotherapy with ICIs represents a promising therapeutic strategy for LKB1-deficient lung cancers.