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Page 10 of 20 Zhang et al. Cancer Drug Resist 2024;7:34 https://dx.doi.org/10.20517/cdr.2024.59

circRNAs mediate drug resistance of NPC
Patients with distant metastases of NPC exhibit specific overexpression of circIPO7, and its knockdown
[138]
enhances sensitivity to CDDP treatment by inhibiting YBX1 nuclear localization . Furthermore, studies
have reported an association between aging and tumor metastasis and chemoresistance. Notably,
circWDR37 facilitates the activation of PKR, leading to the initiation of SASP transcription through NF-κB,
[139]
thereby promoting metastasis and chemoresistance in NPC . A separate study demonstrated the role of
circCRIM1 as a ceRNA in promoting metastasis and conferring docetaxel chemoresistance in NPC through
the upregulation of FOXQ1. Additionally, the study successfully developed a prognostic model based on
circCRIM1 expression and TMN staging to assess the risk of NPC metastasis .
[80]

circRNAs mediate drug resistance of HNC
CDDP resistance in HNC is strongly linked to autophagy, a process essential for maintaining protein
homeostasis, organelle integrity, cellular homeostasis, cell viability, and the degradation/recirculation of
various cellular components to the lysosome [140,141] . In OSCC, significant upregulation of circAP1M2 leads to
[51]
the induction of autophagy-associated CDDP resistance via the miR-1249-3p/ATG9A axis . In LSCC,
circPARD3 hinders autophagy by serving as a sponge for miR-145-5p, which activates the PRKCI/Akt/
[142]
mTOR pathway, thereby promoting tumor progression and contributing to CDDP resistance . TC is
characterized by the promotion of autophagy and increased CDDP resistance due to the regulatory effects
of circEIF6 on the miR-144-3p/TGF-α axis [Table 4 and Figure 3]. Interestingly, autophagy exhibits
[143]
dynamic tumor-suppressive or tumor-promoting roles in diverse contexts and stages of cancer
development . Therefore, further research is needed to better define the specific roles of autophagy in
[144]
various types and stages of cancer, and to gain a deeper understanding of how tumors rely on autophagy.
Furthermore, several studies have demonstrated the reciprocal regulation between circRNAs and
N6-methyladenosine (m6A) modifications in HNC, highlighting their potential impact on cancer
progression and treatment response [145-148] . Additionally, there have been reports indicating the upregulation
of circCUX1 expression in radiotherapy-resistant hypopharyngeal SCC patients, and the knockdown of
[149]
circCUX1 has been shown to enhance the sensitivity of hypopharyngeal cancer cells to radiotherapy .

FUTURE PERSPECTIVES
Based on our persistent dedication to this field and thorough literature research, we firmly assert that the
following areas of research exhibit dynamism and merit sustained attention.

Ferroptosis
Ferroptosis, also known as iron-induced apoptosis, is a type of intracellular cell death that relies on iron and
is distinguished by the excessive accumulation of reactive oxygen species (ROS) and lipid peroxidation. It is
distinct from apoptosis, necrosis, and autophagy [150,151] . Numerous studies have reported that tumor cells can
enhance their defense mechanisms against oxidative stress by inhibiting ferroptosis, ultimately promoting
their survival and drug resistance [152,153] . Studies have demonstrated that in NPC, infection with EBV leads to
the upregulation of GPX4 expression, resulting in the inhibition of ferroptosis. Consequently, the elevated
levels of GPX4 contribute to the progression of NPC and its resistance to chemotherapy through the
activation of the TAK1-JNK and IKK/NF-κB signaling pathways. Moreover, clearance of the EBV genome
[154]
has been shown to enhance the sensitivity of NPC cells to ferroptosis . Artesunate exhibits selective
cytotoxicity against HNC cells. In specific cases of CDDP-resistant HNC, inhibiting the Nrf2-ARE pathway
enhances the sensitivity of these cells to artesunate and reverses their resistance to ferroptosis [155,156] .
Additional studies have further demonstrated that inhibiting GLRX5 renders CDDP-resistant HNC cells
more susceptible to ferroptosis . Furthermore, the upregulation of HMGA1 in ESCC serves as a crucial
[157]
factor responsible for CDDP resistance by suppressing ferroptosis. This effect is achieved through
HMGA1’s role in maintaining intracellular redox homeostasis via its assistance to ATF4 in activating