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Table 1. Advantages of targeting non-coding RNAs to overcome tumor drug resistance
Aspect Summary Ref.
Complexity of ncRNAs form intricate regulatory networks that influence various biological processes, including gene [18]
regulatory networks expression, signal transduction, and the cell cycle. Targeting these nodes can impact tumor growth and drug
resistance
Specific role ncRNAs may be uniquely expressed in tumor cells or play critical roles in tumor development and drug [19]
resistance, enabling the development of targeted therapies
Multi-target ncRNAs can affect multiple signaling pathways and biological processes simultaneously, making them suitable [20]
intervention for multi-target interventions to address multidrug resistance
Drug tolerance ncRNAs may have a lower risk of tolerance development compared to protein targets due to their distinct [21]
regulatory mechanisms
Diverse treatment ncRNAs can act as direct drug targets, carriers, or therapeutic agents, offering a range of treatment strategies [16]
strategies
New drug discovery Research on ncRNAs provides new molecular targets for drug development, aiding in the discovery of novel [22]
antitumor agents
Personalized medicine ncRNA-based biomarkers can guide personalized treatment plans, helping physicians select the most suitable [23-
therapy for individual patients 25]
Combination therapy ncRNAs can be combined with other therapies (e.g., chemotherapy, radiotherapy, immunotherapy) to improve [26]
efficacy and reduce drug resistance
Treatment monitoring ncRNA expression levels can be used as biomarkers to monitor treatment efficacy, tumor response, and drug [27]
and evaluation resistance development
Gene editing Gene editing technologies like CRISPR/Cas9 offer tools for targeting ncRNAs, enabling precise regulation of [28]
applications their expression and influencing drug resistance
ncRNAs: Non-coding RNAs.

mRNA degradation or inhibiting translation [29-31] . Numerous studies have demonstrated the involvement of
miRNA dysregulation in the development and chemoresistance of HNC [32-34] .

miRNAs dysregulation is closely related to chemoresistance in HNC
Research indicates a close association between miRNA dysregulation and chemoresistance in HNC. Zhang
et al. observed the downregulation of miR-216a-5p and ZEB1 in laryngeal squamous cell carcinoma (LSCC)
tissues. Moreover, they demonstrated that overexpression of miR-216a-5p could reverse the malignant
phenotype and cisplatin (CDDP) resistance of LSCC cells by targeting ZEB1 . Gao et al. identified that
[35]
circ_0109291 promoted CDDP resistance in oral squamous cell carcinoma (OSCC) cells. They elucidated its
mechanism by showing that circ_0109291 sponged miR-188-3p, leading to upregulation of ABCB1
expression . Cao et al. revealed that HOTAIR induced CDDP resistance in nasopharyngeal carcinoma
[36]
(NPC) by sponging miR-106a-5p, consequently upregulating SOX4 expression . The miR-200 family
[37]
constitutes a pivotal group of miRNAs implicated in the regulation of epithelial-mesenchymal transition
(EMT). Their downregulation is closely linked to chemoresistance in HNC. For instance, reduced
expression of Let-7, miR-200, and miR-203 correlates with docetaxel resistance in OSCC [38-42] . Moreover, the
miR-200c/c-myc negative feedback loop orchestrates EMT, stemness, and chemoresistance in NPC [43,44] .
Additionally, dysregulation of miR-138, miR-222, miR-101, miR-23a, miR-214, and various other miRNAs
has been associated with chemoresistance in HNC [45-47] . In summary, the dysregulation of specific miRNAs
plays a key role in the acquired chemoresistance of HNC.

miRNAs affect chemoresistance by regulating autophagy signaling pathways
Autophagy and miRNAs are intricately linked to chemoresistance in HNC. H19 induces CDDP resistance
in LSCC cells by upregulating the expression of autophagy-related proteins Atg5 and Beclin1 through the
[48]
miR-107/HMGB1 axis . MiR-155 inhibitor-loaded exosomes reverse CDDP resistance in OSCC by
inducing autophagy through the upregulation of FOXO3a . Yang et al. found that upregulated miR-214
[49]
expression could inhibit autophagy in OSCC cells by targeting autophagy-related genes ULK1 and ATG5,