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Cheng et al. Cancer Drug Resist. 2025;8:46 Page 17 of 28

catalase, along with reduced O consumption via metformin. Furthermore, metformin downregulated PD-L1
2
expression in tumor cells, markedly enhancing T cell cytotoxicity . Triphenylphosphine cations targeting
[158]
mitochondria were conjugated to the antineoplastic agent lonidamine, and the conjugate was encapsulated
into liposomes. These liposomes reversed hypoxia, downregulated PD-L1 expression by activating
AMP-activated protein kinase, and sensitized tumors to radiotherapy [159] . In vivo, the combination of these
liposomes with radiotherapy almost completely suppressed tumor growth, achieving inhibition rates of
79.6% ± 5.2% by day 14. A mitochondria-targeted heptamethine cyanine photodynamic therapy dye (MHI)
was conjugated with tamoxifen, an inhibitor of mitochondrial complex I, and the conjugate further
self-assembled with albumin. The resulting nanoparticles effectively alleviated tumor hypoxia, inhibited
PD-L1 expression, and enhanced the efficacy of photodynamic immunotherapy by promoting T cell
infiltration .
[160]
In addition to strategies that reduce oxygen consumption to mitigate hypoxia, other nanoagents have been
developed to generate oxygen. Chen et al. fabricated multienzyme-mimetic alloy nanosheets composed of
palladium and iron. These nanosheets exhibited peroxidase- and catalase-like activities, as well as the ability
to induce ferroptosis. They counteracted hypoxia through catalase-like O generation, resulting in decreased
2
HIF-1α expression, reduced infiltration of M2-like macrophages and Tregs, and suppressed PD-L1
expression. Moreover, the nanosheets possessed second near-infrared phototherapy and photoacoustic
imaging capabilities, and combined with their ferroptosis induction and TME-modulating properties, they
synergized effectively with anti-PD-L1 treatment [161] . A multifunctional nanocomposite consisting of
defect-rich tungsten trioxide (WO ) and ferrocene-folic acid was synthesized via sequential reactions of
3-x
ferrocenyl chloride with folate and WO . This composite triggered ICD through synergistic photothermal
3-x
and chemodynamic therapy, while simultaneously decomposing H O to O via the Fenton reaction, thereby
2
2
2
reducing hypoxia-induced PD-L1 expression .
[162]
A liposomal nanovehicle co-loaded with copper oleate, a Fenton catalyst, and the HIF-1 inhibitor acriflavine
downregulated PD-L1 expression by inhibiting HIF-1, while copper oleate-mediated chemodynamic therapy
was enhanced by suppression of the HIF-1 signaling pathway . Monomethoxy PEG-poly(lactic-co-glycolic
[163]
acid) nanoparticles encapsulating the hypoxia-activated prodrug evofosfamide (TH-302), a 2-nitroimidazole
derivative that releases bromo-isophosphoramide mustard, effectively ameliorated tumor hypoxia, reduced
HIF-1α and PD-L1 expression, and facilitated infiltration of CD8 T cells, thereby potentiating anti-PD-1
+
therapy [164] . Combined nanoparticles co-loaded with TH-302 and an anti-PD-L1 antibody significantly
reduced tumor volume (P <​ 0.01 vs. anti-PD-1 group) and tumor weight (P <​ 0.001 vs. anti-PD-1 group).
Clustered regularly interspaced short palindromic repeats/Cas9 (CRISPR/Cas9) technology has also emerged
as a promising approach for stably altering gene expression. Silica-decorated silver sulfide quantum dots,
which emit in the second near-infrared window, were engineered to deliver CRISPR/Cas9
ribonucleoproteins via a hypoxia-responsive azo bond. The quantum dots were encapsulated by amphiphilic
tirapazamine-modified hyaluronic acid polymers, which were further cross-linked with disulfide bonds.
Under hypoxic conditions, activation of the tirapazamine prodrug and spatiotemporal release of the
CRISPR/Cas9 ribonucleoprotein were achieved. This strategy significantly alleviated hypoxia by depleting
HIF-1α and activating tirapazamine, thereby disrupting PD-1/PD-L1 signaling and enhancing T
cell-mediated antitumor immunity .
[165]

Nanoparticles for tumor vascular normalization
Nanoparticles for tumor vascular normalization have emerged as a rational strategy to alleviate tumor
hypoxia and overcome resistance to immunotherapy. A unique peptide amphiphile was developed by
incorporating antiangiogenic secreted protein acidic and rich in cysteine (SPARC) FSEC peptide and
PD-L1-inhibiting PPA peptide sequences, linked via a legumain-cleavable amino acid sequence, and further
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