Tumor cell-intrinsic Piezo2 drives radioresistance by impairing CD8+ T cell stemness maintenance

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Mechanosensitive ion channels' role in radiation response and antitumor immunity is poorly understood.
• The mechanical force sensor Piezo2's involvement in cancer radiotherapy has not been previously investigated.

Purpose of the Study:

• To investigate the role of Piezo2 in tumor radioresistance.
• To explore the underlying mechanisms linking Piezo2 to antitumor immunity and therapeutic sensitivity.

Main Methods:

• Utilized Piezo2 knockout models in tumor cells.
• Analyzed the JAK2/STAT1/IRF-1 signaling pathway and Interleukin-15 (IL-15) expression.
• Assessed CD8+ T cell infiltration, function, and stem cell-like properties.
• Correlated Piezo2 expression with clinical data from rectal adenocarcinoma patients undergoing radiotherapy.

Main Results:

• Piezo2 was upregulated in tumor cells post-radiation, contributing to radioresistance.
• Piezo2 knockout enhanced radiotherapy's tumor growth suppression.
• Loss of Piezo2 induced tumor cell IL-15 expression via the JAK2/STAT1/IRF-1 axis.
• Increased IL-15 augmented CD8+ T cell effector and stem cell-like properties, reducing exhaustion.
• Tumor Piezo2 expression negatively correlated with CD8 infiltration and patient radiosensitivity.

Conclusions:

• Tumor-intrinsic Piezo2 promotes radioresistance by inhibiting the IRF-1/IL-15 axis, impairing CD8+ T cell-mediated antitumor immunity.
• Targeting Piezo2 presents a potential strategy to enhance radiotherapy efficacy in radioresistant cancers.