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Cheng et al. Cancer Drug Resist. 2025;8:46 Page 11 of 28

PD-1 antibody therapy by positively modulating the hypoxic milieu . A nanoplatform composed of copper
[132]
peroxide nanoparticles, which generate oxygen in acidic environments, an outer red blood cell membrane
coating, and a protoporphyrin-conjugated chimeric peptide integrated into the cell membrane via
electrostatic interaction was shown to reverse hypoxia through oxygen production. This platform
re-educated TAMs toward the M1 phenotype and increased T lymphocyte infiltration, thereby amplifying
protoporphyrin-triggered immunogenic cell death (ICD) . Hybrid nanovesicles formed by integrating M1
[133]
macrophages-derived exosomes (M1-Exos) with AS1411 aptamer-conjugated liposomes (AApt-Lips) were
employed to deliver perfluorotributylamine as an oxygen carrier and the photosensitizer IR780. These hybrid
vesicles enhanced tumor photodynamic immunotherapy by repolarizing TAMs toward the M1 phenotype
and promoting T lymphocyte infiltration [134] [Figure 4]. Polydopamine nanoparticle-stabilized oxygen
microcapsules increased oxygen concentration in hypoxic tumor regions and significantly improved the
efficacy of anti-PD-1 antibody therapy against pancreatic ductal adenocarcinoma by reducing TAM
infiltration and polarizing M2 macrophages to M1 .
[135]

Losartan, which can reduce solid stress and improve oxygen supply, was combined with doxorubicin
liposomes to induce ICD, reprogram TAMs, and enhance PD-1 antibody efficacy. This combination
successfully overcame the immunosuppressive microenvironment [149] . Self-assembled nanocomposites of
atovaquone, protoporphyrin IX, and stabilizers mediated photodynamic ICD induction and relieved hypoxia
through atovaquone-mediated inhibition of mitochondrial respiratory chain complex III, which decreased
oxygen consumption and promoted TAM polarization toward the M1 phenotype .
[136]

Catalase-loaded calcium carbonate nanoparticles induced Ca overload, activated T cell-mediated immunity,
2+
and repolarized TAMs to the M1 phenotype by consuming protons in the TME and generating oxygen from
ROS decomposition catalyzed by catalase, further boosting immune responses [137] . Fe-doped,
doxorubicin-loaded Cu S nanomaterials modified with hyaluronic acid and polyethylene glycol (PEG)
2-x
exhibited catalase-like activity, efficiently decomposing H O to produce O , alleviating hypoxia, and
2
2
2
repolarizing TAMs to M1. Combined with anti-PD-L1 nanobody therapy, these nanomaterials elicited
sustained T cell responses and immune memory [138] . Zhang et al. developed a chiral nanoassembly
comprising up-conversion nanoparticles and porphyrin metal-organic frameworks for the delivery of chiral
Zn and biotin. This assembly facilitated H O degradation into O , depleted lactate, reduced HIF-1α
2
2
2
expression, and reprogrammed TAMs, enhancing photodynamic ICD and adaptive immunity [139] . In vivo,
this assembly promoted dendritic cell maturation from 11.7% in controls to 23.9%, and increased CD8 and
+
CD4 T cells from 9.15% and 10.4% to 27.5% and 27.3%, respectively. A MnO -based albumin nanoplatform
+
2
co-loading photosensitizer IR780, indoleamine-2,3-dioxygenase 1 (IDO-1) inhibitor NLG919, and paclitaxel
dimer strengthened the activity of IR780 and paclitaxel dimer via MnO -catalyzed oxygen production,
2
alleviated hypoxia, and reduced intratumoral TAMs and PD-L1 expression . Multifunctional nanoparticles
[140]
with a MnO core and a shell of lipids and poly(lactic-co-glycolic acid) for sorafenib delivery alleviated
2
hypoxia via MnO -mediated H O decomposition, reduced TAM infiltration, and promoted macrophage
2
2
2
polarization to M1, enhancing the efficacy of PD-1 antibody therapy and whole-cell cancer vaccines [141] .
Cu-based carbon dots targeted tumors to induce ferroptosis and ICD, and O produced via Fenton-like
2
decomposition of H O mitigated hypoxia, decreased HIF-1α expression, and reprogrammed TAMs to the
2
2
M1 phenotype, thereby enhancing antitumor immune responses .
[142]
Nanomaterials for directly repolarizing TAMs
A phospholipid- and PEG-enveloped tannic acid core was developed for the delivery of the CXCR4
antagonist BPRCX807. The nanoagent reprogrammed TAMs toward an M1 phenotype, promoted T cell
infiltration, and enhanced the efficacy of PD-1 blockade and whole-cancer-cell vaccines . KIRA6, an
[56]
inhibitor of the hypoxia-activated IRE1-XBP1 pathway, was encapsulated in a reductive nanoemulsion

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