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Page 12 of 20 Zhang et al. Cancer Drug Resist 2024;7:34 https://dx.doi.org/10.20517/cdr.2024.59

Nanodrugs
CDDP, carboplatin, and oxaliplatin are commonly employed in tumor therapy. Nevertheless, their clinical
utility is severely restricted due to the side effects associated with platinum drugs, including poor selectivity,
high systemic toxicity, and drug resistance . A novel CDDP nanocarrier system with dual targeting
[169]
properties has been developed. This system selectively attaches to the A54 receptor, which is highly
expressed on the cell surface of hepatocellular carcinoma (HCC) cells. Additionally, it utilizes the drug-
resistance gene NOR1 shRNA as a piggyback mechanism to enable precise tumor-targeted therapy and
[170]
overcome drug resistance . Numerous studies have also highlighted the effectiveness of platinum
nanocarriers in reducing systemic toxicity and overcoming drug resistance [171-174] . Currently, there is
considerable research focus on strategies involving nanomedicines for regulating ferroptosis, as well as
nanomedicines utilizing non-coding RNAs as carriers to target tumors [85,175-179] .

Exosomes
Exosomes are nanovesicles derived from cells, ranging in size from 30 to 150 nm. They are released when
multivesicular bodies fuse with the cell surface and play a crucial role in intercellular communication by
transporting nucleic acids, proteins, and lipids. Furthermore, exosomes can activate signaling pathways in
target cells [180,181] . In recent years, there has been significant interest in the role of exosomes carrying non-
coding RNA in tumor drug resistance [93,163,182-185] . Several studies have reported that intervention with RNA
carried by exosomes can potentially overcome tumor chemoresistance [61,186,187] . For instance, CAFs emerge as
crucial regulators of CDDP resistance in HNC. They achieve this by transporting functional miR-196a from
CAFs to tumor cells through exosomes . Although our understanding of the role of RNAs carried within
[62]
exosomes in the mechanisms of drug resistance in HNC is still in the early stages, exosomal circRNAs have
emerged as innovative genetic information carriers. These molecules enable communication between tumor
cells and cells in the microenvironment, thereby regulating critical aspects of cancer progression. As a result,
they contribute significantly to chemotherapeutic drug resistance across different types of cancer. Based on
this, synthetic exosomal circRNA holds the potential to introduce new avenues for cancer therapy [188,189] .

Proteolysis-targeting chimeras
Proteolysis-targeting chimeras (PROTACs) are emerging as promising therapeutic modalities for the
degradation of disease-causing proteins. They are composed of a ligand that binds to a protein of interest
(POI) and another ligand that recruits the E3 ubiquitin ligase. This recruitment induces chemical proximity
between the POI and the E3 ligase, resulting in ubiquitination and subsequent degradation of the POI
through the ubiquitin-proteasome system [190-193] .PROTACs have been developed to target several proteins,
including PD-L1, BTK, STAT3, EGFR, MEK1/2, VEGFR2, FLT-3, and SHP2 . These compounds offer
[194]
advantages such as high enzymatic reaction efficiency, overall degradation of target proteins, and the ability
to target small-molecule non-druggable proteins. Several studies have reported the successful inhibition of
HNSCC growth and metastasis using PROTAC technology [195,196] . This finding highlights the importance of
continued attention to PROTAC and related technologies due to their ability to specifically degrade
oncogenic proteins or RNAs [194,197,198] .

CONCLUSION
In summary, chemotherapy, targeted therapy, and immunotherapy are crucial components of integrated
tumor therapy. However, drug resistance significantly limits the effectiveness of clinical drug therapy for
HNC. Non-coding RNA dysregulation plays a critical role in the known mechanisms of drug resistance in
HNC. It is essential to continually focus on new technologies and theories to address the challenges in HNC
drug resistance research. This includes the construction or utilization of clinical databases similar to UK
biobank , and integrating clinical information with multi-omics sequencing data. These approaches aim
[199]
[200]
to establish a robust foundation for further research on integrative oncology treatment . Additionally,