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Page 14 of 28 Cheng et al. Cancer Drug Resist. 2025;8:46

complex class I (MHC I) expression in carcinoma cells, facilitating their recognition by T cells . In vivo, the
[150]
hydrogel achieved a 78% tumor inhibition rate and reduced pulmonary metastatic nodules by 26-fold
compared with the control group. The construction of the injectable hydrogel and its mechanism in
reversing T cell exhaustion are presented in Figure 5. A stable water-in-oil lipiodol Pickering emulsion
stabilized with calcium phosphate nanoparticles was fabricated to encapsulate L-arginine, which modulates T
cell metabolism. The emulsion neutralized the acidic TME via calcium phosphate and regulated T cell
metabolism through L-arginine, thereby synergistically reversing CD8 T cell exhaustion and tumor
+
immunosuppression . In non-small cell lung cancer, hypoxia and lipid rafts in the cell membrane hinder T
[151]
cell infiltration and impair their function. An albumin-bound fluvastatin nanoformulation simultaneously
alleviated hypoxia and disrupted lipid raft integrity, restoring T cell infiltration and enhancing cytotoxic T
cell function, ultimately improving the efficacy of anti-PD-1 antibody therapy .
[152]

Manganese dioxide-albumin nanoparticles were used as drug carriers to load buformin (an inhibitor of
mitochondria-associated oxidative phosphorylation) and methylene blue (a photodynamic therapy agent
with PD-1 inhibition activity) via electrostatic absorption. Hypoxia was alleviated by inhibiting O 2
consumption with buformin and generating O through MnO activity, thereby enhancing photodynamic
2
2
therapy. Furthermore, the manganese dioxide-albumin complex strengthened ICD, inhibited the
PD-1/PD-L1 axis, and relieved T cell exhaustion . Cancer cell membrane - encapsulated manganese oxide
[153]
nanozymes with multienzyme-mimicking activity exhibited peroxidase- and oxidase-like functions and
induced ICD. The released Mn promoted dendritic cell maturation and TAM reprogramming, while
2+
catalase-like activity relieved tumor hypoxia. Collectively, these effects reversed the immunosuppressive
TME and significantly increased the proportions of CD8 cytotoxic T lymphocytes and CD4 T cells within
+
+
tumors. Combination therapy with the manganese oxide nanozyme and PD-1 antibody further enhanced T
cell-mediated antitumor immunity [154] . Liposomes were also engineered to co-deliver metformin, which
downregulates PD-L1 expression via AMP-activated protein kinase-mediated ER-associated protein
degradation, and IR775, a photodynamic therapy agent. These liposomes alleviated tumor hypoxia to boost
ROS production, reduced PD-L1 expression, and reversed T cell exhaustion .
[155]

CaO nanoparticles encapsulated with EL4 cell membranes effectively rescued T cells from exhaustion by
2
increasing glucose availability for cytotoxic lymphocytes and decreasing lactic acid accumulation through
Ca -mediated blockade of glycolysis. They also alleviated hypoxia, scavenged TGF-β1, and blocked PD-L1
2+
via cell membrane receptors [156] . In vivo, treatment with CaO nanoparticles and 2-deoxyglucose increased
2
tumor-infiltrating IFN-γ CD8 T cells by 6.1-fold, demonstrating effective rescue of CD8 T cells from
+
+
+
exhaustion in the immunosuppressive TME. Remarkably, this combination also reduced MDSCs and Tregs
by 30.6% and 28.6%, respectively.

Nanomaterials retarding immune escape
The PD-1/PD-L1 axis is a key pathway mediating immune evasion, and numerous nanoformulations have
been developed to alleviate hypoxia or inhibit PD-1/PD-L1-mediated immune escape. As depicted in Figure
6, a hybrid nanoadjuvant was fabricated by loading triphenylphosphine-derived metformin - an agent that
decreases oxygen consumption by actively targeting mitochondria and inhibiting complex I of the
respiratory chain - into albumin-templated manganese dioxide nanoparticles through positive and negative
adsorption. Tumor hypoxia was alleviated by increased O production catalyzed by MnO and decreased O 2
2
2
consumption induced by metformin-mediated mitochondrial inhibition. In addition, metformin suppressed
TGF-β secretion and reduced membrane-localized PD-L1 expression, thereby reversing the
immunosuppressive microenvironment and activating T cells [157] . Liposomes co-loaded with metformin,
catalase, and hematoporphyrin monomethyl ether were designed to relieve hypoxia and enhance the efficacy
of photoimmunotherapy in “cold” tumors. Hypoxia was reversed through H O decomposition catalyzed by
2
2

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