REVIEW article
Front. Cell Dev. Biol.
Sec. Cellular Biochemistry
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1642417
The role and targeting strategies of non-coding RNAs in immunotherapy resistance in oral squamous cell carcinoma
Provisionally accepted
- 1Department of Radiation Oncology, Fengcheng Hospital of Fengxian District, Shanghai, China
- 2Clinical Medical College, Yangzhou University, Yangzhou, China
- 3Hangzhou Institute for Advanced Study, University of Chinese Academy of Science, Hangzhou, China
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Oral squamous cell carcinoma (OSCC) represents a major global health burden, with resistance to immune checkpoint inhibitors (ICIs) posing a significant barrier to effective immunotherapy. Emerging evidence implicates non-coding RNAs (ncRNAs)—including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs)—as pivotal regulators of this resistance. In this review, we discuss how ncRNAs contribute to OSCC immunotherapy resistance by modulating immune checkpoint expression, suppressing anti-tumor T cell function while promoting immunosuppressive Tregs, reprogramming the tumor microenvironment (TME) via metabolic remodeling and myeloid cell regulation, and enhancing intrinsic tumor resistance through epigenetic alterations and cancer stem cell activation. These multifaceted roles highlight the therapeutic potential of targeting ncRNAs. Strategies involve inhibiting oncogenic ncRNAs or restoring tumor-suppressive counterparts, facilitated by advanced delivery methods like nanoparticles or exosomes. Combining ncRNA-based therapies with ICIs offers a promising approach to overcome resistance. Key challenges remain, including precise functional annotation, efficient and specific delivery, experimental validation, biomarker identification, and the design of optimized clinical trials— potentially guided by artificial intelligence and multi-omics approaches. Ultimately, targeting the complex ncRNA networks may offer transformative improvements in immunotherapy outcomes for OSCC patients.
Keywords: Oral squamous cell carcinoma (OSCC), Non-coding RNA (ncRNA), Immunotherapy resistance, Tumor Microenvironment, Targeting strategies
Received: 06 Jun 2025; Accepted: 14 Oct 2025.
Copyright: © 2025 Liang, Zhao, Wang and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xin Wang, wx@ucas.ac.cn
Yuehe Li, luesh@126.com
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.