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Page 20 of 28 Cheng et al. Cancer Drug Resist. 2025;8:46
to play a central role in resistance to immunotherapy. Recent advances in nanotechnology have enabled the
reversal of immunotherapy resistance through nanomaterials targeting the HIF-1α axis. However, several
issues in both basic research and, more importantly, clinical application remain unresolved.
The precise mechanisms and signaling pathways underlying HIF-1α-mediated immunotherapy resistance are
not yet fully understood, and further in-depth molecular studies are required. The metabolism and
long-term safety of nanomaterials - particularly inorganic nanoparticles - remain insufficiently characterized,
necessitating additional investigation. Potential safety risks associated with long-term or repeated
administration of nanoparticles targeting the HIF-1α pathway, especially in the context of chronic
immunotherapy regimens, must be carefully evaluated. Minimizing off-target effects and the accumulation
of nanoparticles in non-target organs is essential for safety, as is the prevention of immune overactivation.
Thus, the optimization of material formulations and the development of more biocompatible nanomaterials
are ongoing priorities.
Tumor hypoxia is characterized by heterogeneity across tumor types and clinical stages, as well as spatial
heterogeneity within individual tumors . Therefore, the design of nanoparticles targeting the hypoxia axis
[17]
with diverse therapeutic strategies should be informed by further fundamental studies in oncology,
pathology, and clinical staging. Moreover, factors influencing the response to immunotherapy are highly
complex and extend beyond tumor hypoxia alone. Integrated strategies to overcome resistance and achieve
personalized treatment represent a promising research direction.
When designing nanomaterials targeting the hypoxia signaling pathway, druggability must also be carefully
considered. The pharmaceutical industry generally follows the principle of “keep it simple, stupid”, and
complex manufacturing processes and standardization challenges hinder the scale-up of nanodrugs from
laboratory to industry. The pharmacokinetics and in vivo behavior of nanomedicines remain poorly defined,
particularly in humans, and urgent, in-depth investigations are required. The complexity of nanoagents has
also prompted regulatory agencies to advocate for more stringent standardization protocols, comprehensive
toxicity profiling, and rigorous efficacy evaluations to ensure safety, potency, and reproducibility.
As of 2025, ClinicalTrials.gov lists no ongoing or completed clinical trials investigating hypoxia and
nanoparticles. This absence is likely due to the challenges of large-scale manufacturing and safety concerns
regarding nanoparticles. Robust preclinical data on safety and efficacy in large-scale animal tumor xenograft
models are essential for clinical translation. To improve clinical prospects, simple and biocompatible
nanosystems targeting the hypoxia pathway should be developed. Well-controlled clinical trials are urgently
needed to define the limitations and therapeutic potential of nanomaterials targeting hypoxia for overcoming
immunotherapy resistance.
In conclusion, cancer immunotherapy still faces major challenges, yet strategies targeting the hypoxia
signaling pathway to overcome resistance have shown encouraging progress in research. We anticipate that
continued basic research on hypoxia and immunotherapy resistance will enable the development of simpler,
safer nanocarriers that can be translated into clinical practice for personalized treatment, ultimately allowing
more patients to benefit from immunotherapy.
DECLARATIONS
Authors’ contributions
Writing - review and editing: Cheng X, Wang P
Drafting and revising the manuscript: Lyu H
Editing, supervision, and conceptualization: Lee Y, Yoon J, Dong H
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