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Cheng et al. Cancer Drug Resist. 2025;8:46 Page 13 of 28

alleviated hypoxia, thereby enhancing the infiltration of M1 macrophages and T cells . Sun et al. fabricated
[58]
a hypoxia-responsive PEGylated Fe-5,5’-azosalicylic acid nanoscale coordination polymer. In the hypoxic
milieu, cleavage of the azobenzene bond by azo-reductase released 5-azosalicylic acid and ferric ions, which
triggered apoptosis. Meanwhile, 5-azosalicylic acid, as a cyclooxygenase-2 inhibitor, suppressed
prostaglandin E expression, while Fe re-educated TAMs toward the M1 phenotype. Collectively, these
3+
2
effects remodeled the immunosuppressive microenvironment to elicit an immune response . Biomimetic
[143]
nanoparticles coated with hybrid cancer-macrophage cytomembranes were designed to load semiconducting
polymers, atovaquone, and TMP195 which can repolarize TAMs. These nanoparticles alleviated hypoxia,
reprogrammed TAMs toward the M1 phenotype, induced ICD, and converted the TME from a “cold” to a
“hot” state [144] . In primary tumors, the proportion of CD3 CD8 T cells after treatment with the biomimetic
+
+
nanoparticles plus ultrasound reached 16.8% ± 0.7%, which was significantly higher than that in the control
group treated with ultrasound alone (5.9% ± 0.1%). The numbers of CD3 CD8 T cells in lymph nodes and
+
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distant tumors were also markedly increased.
Nanomaterials for depleting TAMs
Direct depletion of TAMs represents another strategy to counteract their role in inducing resistance to
immunotherapy. A hemoglobin-poly(ε-caprolactone) conjugate self-assembly was designed to co-deliver
doxorubicin and oxygen. The hemoglobin component specifically bound to M2 TAMs via the CD163
receptor, while the loaded doxorubicin effectively killed TAMs. Additionally, oxygen released by hemoglobin
alleviated hypoxia and reduced macrophage recruitment [145] . In vivo, this self-assembled system reduced
TAMs from 70.8% ± 7.7% in the control group to 31.3% ± 4.2% (P <​ 0.001), owing to the combined effects of
TAM targeting and hypoxia mitigation. Furthermore, liposomes modified with the TAM-targeting peptide
M2pep were used to encapsulate zoledronic acid and the sonosensitizer hematoporphyrin monomethyl
ether. The combination of sonodynamic therapy and zoledronic acid effectively depleted M2-like TAMs and
elicited multi-faceted antitumor immune responses, including relief of tumor hypoxia, increased production
of immune-promoting cytokines, and reduced levels of immunosuppressive cytokines .
[146]
Nanomaterials targeting HIF-1α to re-educate TAMs
Liposomes delivering tanespimycin, a potential ICD inducer, were developed. In addition to inducing ICD,
tanespimycin acted as a potent Hsp90 inhibitor, downregulating HIF-1α (an Hsp90 client protein), reducing
TAMs and MDSCs within the TME, and enhancing the efficacy of immune checkpoint blockade therapy in
triple-negative breast cancer [147] . In another approach, the hypoxia pathway inhibitor docosahexaenoic acid
was conjugated to fucoidan via a cleavable selenylsulfide bond to form micelles, with carfilzomib
encapsulated in their hydrophobic core. These micelles induced ICD, suppressed HIF-1α expression,
inhibited TAM infiltration and M2 polarization, thereby remodeling the immunosuppressive milieu and
enhancing antitumor immune responses .
[148]

Nanomaterials inhibiting T cell exhaustion
Various nanoparticles targeting hypoxia-related pathways and alleviating the hypoxic TME have been
developed to inhibit T cell exhaustion. For example, a hydrogel was generated in situ within tumors by
leveraging oxidized sodium alginate decorated cancer cell membrane vesicles as a gelator. Axitinib was
embedded within the lipid bilayer of the membrane, while 4-1BB antibody and the proprotein convertase
subtilisin/kexin type 9 inhibitor PF-06446846 were encapsulated in the hydrogel cavities. The cancer cell
membrane antigens elicited an immune response, activating and recruiting T cells to the tumor. The released
4-1BB antibody bound to the costimulatory receptor 4-1BB on T cells and enhanced mitochondrial
biogenesis, overcoming exhaustion via upregulation of peroxisome proliferator-activated receptor-γ
coactivator-1α. Axitinib, a vascular endothelial growth factor receptor (VEGFR) inhibitor, alleviated hypoxia
and further prevented T cell exhaustion. Additionally, PF-06446846 enhanced major histocompatibility

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