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Page 2 of 28 Cheng et al. Cancer Drug Resist. 2025;8:46

Finally, the prospects and challenges of translating nanomedicine-based drug delivery systems into clinical practice
for overcoming immunotherapy resistance are outlined.

INTRODUCTION
In recent decades, immunotherapy has emerged as a major treatment strategy for cancer, complementing
traditional approaches such as chemotherapy, surgery, radiotherapy and targeted therapy. Patients now
benefit from a wide range of immunotherapeutic approaches. However, despite these advances,
immunotherapy still faces the profound challenge of low response rates , with resistance representing the
[1]
primary cause of treatment failure.

The tumor microenvironment (TME) is a highly complex ecosystem composed of diverse immune cells,
stromal cells, fibroblasts, cytokines, chemokines, extracellular matrix components, and blood vessels . The
[2]
TME is characterized by features such as low pH, hypoxia, abnormal vasculature, elevated interstitial
pressure, a dense extracellular matrix, and immunosuppression. These features not only support neoplasm
initiation, progression, infiltration, and metastasis but also drive resistance to cancer therapies . Hypoxia, a
[3]
defining hallmark of the tumor milieu, has been shown to play a central role in resistance to chemotherapy
and radiotherapy [4,5] . Increasing evidence also demonstrates that hypoxia promotes resistance to
immunotherapy through multiple mechanisms [6-8] , making it a critical focus in efforts to overcome
immunotherapy resistance. Hypoxia-inducible factor-1α (HIF-1α) and its signaling pathway are key
mediators that enable cellular adaptation to hypoxic conditions, promote immunosuppression, and drive
tumor progression and resistance to immunotherapy .
[9]

Over the past few decades, nanotechnology has achieved remarkable progress, leading to the approval and
clinical application of various nanodrugs, including Doxil, Abraxane, Marqibo, and Onivyde, for cancer
treatment . Nanodrugs offer multiple therapeutic advantages: they improve the solubility of hydrophobic
[10]
drugs, stabilize labile agents, regulate pharmacokinetics and tissue distribution, enable both passive and
active targeting through surface modification, and reduce drug resistance while minimizing toxicity [10-12] .
Importantly, hypoxia restricts the penetration of therapeutic agents into poorly vascularized tumor regions.
Nanomaterials, with their enhanced penetration and retention properties, provide a promising platform for
effective drug delivery under these conditions . This review highlights the role of the HIF-1α signaling
[13]
pathway in mediating immunotherapy resistance, including its involvement in macrophage polarization
toward the M2 phenotype, T cell exhaustion, immune evasion, and angiogenesis. We further discuss
potential strategies to overcome resistance by targeting the HIF-1α pathway, evaluate the opportunities and
challenges of nanomedicine in this context, and explore future research directions. Ultimately, we aim to
provide meaningful insights and practical recommendations to advance cancer immunotherapy.

HIF STABILITY MODULATION AND ITS ROLE IN RESISTANCE TO CANCER IMMUNOTHERAPY
Tumor cells consume large amounts of nutrients and oxygen due to their uncontrolled proliferation.
Although abnormal and impaired neovasculature develops in an attempt to increase the supply of oxygen
and nutrients, this supply remains insufficient to meet tumor demands . The hypoxia-inducible factor
[14]
(HIF) family, a group of transcriptional regulators, serves as a key modulator of cellular adaptation to
hypoxic stress. HIF is a heterodimeric complex with a basic helix-loop-helix structure, composed of an
oxygen-sensitive α subunit and a ubiquitously expressed β subunit . To date, three α isoforms have been
[15]
identified - HIF-1α, HIF-2α, and HIF-3α - which differ in tissue distribution and gene targets . HIF-1α, a
[16]
master regulator of the hypoxic response, is constitutively expressed, whereas HIF-2α is restricted to specific
tissues such as hepatocytes and is exclusive to vertebrates . HIF-3α is also present in certain cells, though its
[17]

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