Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress

Area of Science:

• Oncology
• Immunology
• Epigenetics

Background:

• Histone H3 lysine 9 trimethylation (H3K9me3) demethylase KDM4A is crucial for squamous cell carcinoma (SCC) progression.
• Activating tumor-cell-intrinsic immunity is key for effective cancer immunotherapy.

Purpose of the Study:

• To investigate the role of KDM4A inhibition in promoting antitumor immunity in SCC.
• To explore the mechanistic link between KDM4A inhibition, DNA replication stress, and immune activation.
• To evaluate the synergistic effect of KDM4A inhibition and PD-1 blockade in SCC treatment.

Main Methods:

• Inhibition of KDM4A in SCC models.
• Analysis of heterochromatin compaction and DNA replication stress.
• Assessment of cGAS-STING signaling pathway activation.
• Evaluation of CD8+ T cell recruitment and activation.
• In vivo lineage tracing studies.

Main Results:

• KDM4A inhibition led to heterochromatin compaction and induced DNA replication stress in SCC cells.
• This stress activated the intrinsic cGAS-STING immune signaling pathway via cytosolic DNA accumulation.
• Combined KDM4A inhibition and PD-1 blockade suppressed SCC growth and metastasis.
• The combination therapy effectively eliminated cancer stem cells in vivo.
• KDM4A inhibition enhanced CD8+ T cell responses.

Conclusions:

• Targeting KDM4A is a viable strategy to activate antitumor immunity in SCC.
• KDM4A inhibition potentiates PD-1 blockade immunotherapy by exacerbating replication stress.
• This dual approach offers a promising therapeutic avenue for SCC by targeting cancer stem cells and enhancing immune response.