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Page 18 of 28 Cheng et al. Cancer Drug Resist. 2025;8:46

self-assembled into nanostructures through grafting with hydrophobic octadecylamine tails. The
antiangiogenic peptide promoted vascular normalization, thereby enhancing intratumoral infiltration of
CD8 T cells and NK cells while reducing tumor hypoxia. At the same time, inhibition of PD-L1 relieved
+
immune suppression and enabled an effective antitumor immune response [166] . Polydopamine, which can
trigger photothermal therapy and induce ICD, was employed to deliver gambogic acid and further
camouflaged with 4T1 cell membranes to construct a biomimetic immunostimulatory nanomodulator.
Gambogic acid, released in response to the acidic TME, suppressed heat shock proteins to synergize
chemo-photothermal therapy with ICD. In addition, gambogic acid inhibited HIF-1α and VEGF, leading to
tumor vascular normalization, reduced hypoxia stress, and improved immune cell infiltration. This
synergistic approach transformed a “cold” tumor into a “hot” tumor and enhanced the efficacy of anti-PD-L1
therapy [Figure 7] [167] . The combined biomimetic nanomodulator, light irradiation, and anti-PD-L1
treatment achieved an impressive tumor inhibition rate of 77.29% (P <​ 0.01 vs. the anti-PD-L1 group), and
the number of lung metastatic foci was reduced to 0.67 ± 0.33, significantly lower than in other groups (P <​
0.01).

Lenvatinib, axitinib, and other tyrosine kinase inhibitors with antiangiogenic activity have also been applied
to normalize tumor vasculature and mitigate hypoxic stress. iRGD (CRGDKGPD)-decorated, pH-responsive
liposomes co-encapsulating lenvatinib and the small-molecule PD-1/PD-L1 inhibitor BMS achieved vascular
normalization, reduced Tregs and MDSCs, promoted CD8 T cell infiltration, and upregulated PD-L1
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expression on cancer cells [168] . Similarly, a novel nanoparticle composed of a biodegradable second
near-infrared fluorescent pseudo-conjugate polymer and lenvatinib alleviated hypoxia through vascular
normalization, thereby improving photodynamic therapy efficacy, T cell infiltration, and dendritic cell
maturation [169] . Co-assembly of lenvatinib, adriamycin, Fe ions, and the natural polyphenol
3+
epigallocatechin-3-gallate normalized tumor vasculature, enhanced T cell infiltration, and reduced Tregs and
PD-L1 expression on tumor cells . A human serum albumin (HSA)-based self-delivery nanoagent was also
[170]
constructed through co-assembly of verteporfin, axitinib, and celecoxib. Axitinib-mediated vascular
normalization reduced tumor hypoxia and reversed VEGF-driven immunosuppression, thereby promoting
infiltration of effector immune cells . Another HSA-based assembly of axitinib, the photosensitizer chlorin
[171]
e6, and the IDO inhibitor dextro-1-methyl tryptophan simultaneously enhanced photodynamic therapy,
alleviated hypoxia, normalized vasculature, and boosted immune cell infiltration, collectively strengthening
immunotherapy efficacy [172] . An injectable thermosensitive PLGA-PEG-PLGA copolymer hydrogel
co-delivering the vascular-disruptive agent combretastatin A4 disodium phosphate and epirubicin promoted
CD8 T cell infiltration and dendritic cell maturation, while reducing MDSCs and Tregs [173] . This hydrogel
+
exerted vascular disrupting effects and achieved a tumor inhibition rate of 92% in vivo compared with the
saline group. In another strategy, a self-assembled conjugate of the photodynamic dye MHI148 with bovine
serum albumin and sorafenib enabled cascade two-step reoxygenation and immune re-sensitization.
Sorafenib decreased oxygen consumption by inhibiting mitochondrial respiration while also increasing
oxygen supply through vascular normalization, thereby enhancing T cell infiltration and reducing PD-L1
expression [174] . Finally, a polymersome-based platform for delivering the cyclic dinucleotide STING agonist
not only promoted vascular normalization and mitigated hypoxia but also upregulated T cell adhesion
molecules, enhanced T cell infiltration, proliferation, and function, and amplified the efficacy of immune
checkpoint inhibitors and adoptive T cell treatment .
[175]

CONCLUSION AND PERSPECTIVES
Immunotherapy has emerged as a crucial therapeutic strategy for cancer, complementing chemotherapy,
surgery, radiotherapy, and targeted therapy, and patients have benefited from a wide range of
immunotherapeutic approaches. Despite its great potential, cancer immunotherapy still faces significant
challenges, with low response rates remaining a major hurdle. The HIF-1α signaling pathway has been shown

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