Targeting the NANOG/HDAC1 axis reverses resistance to PD-1 blockade by reinvigorating the antitumor immunity cycle

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immune checkpoint blockade (ICB) therapy, including programmed cell death protein 1 (PD-1) therapy, has revolutionized cancer treatment.
• However, many patients do not respond effectively due to immune-refractory tumors that impede anti-tumor immune responses.

Purpose of the Study:

• To identify novel molecular targets that restrict anti-tumor immunity and contribute to immune refractoriness.
• To explore the therapeutic potential of targeting these factors in combination with ICB therapy.

Main Methods:

• Analysis of transcriptomic data from cancer patients undergoing PD-1 therapy.
• Establishment and utilization of preclinical mouse models of anti-PD-1 therapy-refractory tumors.
• Investigation of the mechanistic role of NANOG and histone deacetylase 1 (HDAC1) in regulating immune cell infiltration and function.

Main Results:

• NANOG was identified as a key factor restricting the amplification of the anti-tumor immunity cycle, promoting immune refractoriness.
• NANOG was found to reduce T cell infiltration and enhance resistance to cytotoxic T lymphocyte (CTL)-mediated killing through HDAC1-dependent regulation of CXCL10 and MCL1.
• Inhibition of HDAC1 sensitized NANOG-high immune-refractory tumors to PD-1 blockade, restoring anti-tumor immunity.

Conclusions:

• The NANOG/HDAC1 axis represents a critical molecular target for overcoming immune refractoriness in tumors.
• Combining histone deacetylase (HDAC) inhibitors with ICB therapy offers a promising strategy to reverse tumor resistance and enhance treatment efficacy.