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Disrupting immune silence: Noncoding RNAs targeting the programmed cell death protein 1/programmed cell death ligand
Chou-Yi Hsu1, Ahmed Hjazi2, Muath Suliman3
1Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.
Abstract:
PD-1 and PD-L1 are programmed cell death proteins and ligands that form a key axis of immune checkpoints that tumors use to escape immune surveillance. Although immune checkpoint inhibitors that activate this pathway have revolutionized the treatment of cancer, resistance and unpredictable responses to a patient are still significant issues. There is growing evidence that noncoding RNAs (ncRNAs) such as microRNAs, long noncoding RNAs, and circular RNAs are key regulators of PD-1/PD-L1 signaling. These ncRNAs control the PD-L1 expression by directing its mRNA and indirectly maintaining the upstream signaling processes, consequently influencing tumor progression, immune cell activity, and drug responses. This review, based on existing research on the mechanistic functions of ncRNAs in PD-1/PD-L1-based immune suppression, discusses the possibility of using ncRNAs as biomarkers to predict immunotherapy response and as new therapies. We also address opportunities in the field of translation, such as ncRNA-based interventions and combinations with checkpoint blockade, and the challenges, which require resolution to move to the clinical practice. The combination of ncRNA biology and tumor immunology has potential applications in the area of precision immunotherapy and the creation of more meaningful treatment tools against malignancies that are resistant to treatment. SIGNIFICANCE STATEMENT: The current review outlines the regulatory functions of noncoding RNAs in the programmed cell death protein 1/programmed cell death ligand 1 immune checkpoint and highlights their role in tumor immune evasion and therapeutic responses regulation. With an interwoven method of mechanistic understanding and translational approaches, this study outlines noncoding RNAs as potential biomarkers and therapeutic targets and provide new approaches to increment the activity of checkpoint blocks and improve precision cancer immunotherapy.
Insights
Noncoding RNAs (ncRNAs) regulate the PD-1/PD-L1 immune checkpoint, impacting cancer immune evasion and treatment response. ncRNAs show promise as biomarkers and novel therapies for precision immunotherapy.
Area of Science:
- Tumor Immunology
- Molecular Biology
- Cancer Therapeutics
Background:
- Programmed cell death protein 1 (PD-1) and its ligand PD-L1 form crucial immune checkpoints exploited by tumors to evade immune surveillance.
- While immune checkpoint inhibitors targeting PD-1/PD-L1 have transformed cancer treatment, challenges like resistance and unpredictable patient responses persist.
- Noncoding RNAs (ncRNAs), including microRNAs, long noncoding RNAs, and circular RNAs, are increasingly recognized as key regulators of PD-1/PD-L1 signaling.
Purpose of the Study:
- To review the mechanistic roles of ncRNAs in PD-1/PD-L1-mediated immune suppression within tumors.
- To explore the potential of ncRNAs as predictive biomarkers for immunotherapy response.
- To discuss ncRNAs as novel therapeutic targets and strategies for enhancing cancer immunotherapy.
Main Methods:
- Review of existing research on ncRNA functions in PD-1/PD-L1 immune checkpoint regulation.
- Analysis of ncRNA mechanisms controlling PD-L1 expression and upstream signaling.
- Examination of translational opportunities and challenges for ncRNA-based cancer therapies.
Main Results:
- ncRNAs critically influence PD-L1 expression, tumor progression, immune cell activity, and responses to cancer therapies.
- ncRNAs modulate the PD-1/PD-L1 immune checkpoint, affecting tumor immune evasion.
- Mechanistic understanding of ncRNAs provides a basis for developing new biomarkers and therapeutic strategies.
Conclusions:
- ncRNAs are significant regulators of the PD-1/PD-L1 pathway and hold potential as biomarkers for predicting immunotherapy outcomes.
- ncRNA-based interventions offer novel therapeutic avenues, potentially improving the efficacy of checkpoint blockade therapies.
- Integrating ncRNA biology with tumor immunology can advance precision immunotherapy and overcome treatment resistance in malignancies.
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