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Page 6 of 28 Cheng et al. Cancer Drug Resist. 2025;8:46
Figure 1. Mechanisms of TAM-mediated resistance to immunotherapy [60] . TAM: Tumor-associated macrophage.
Moreover, hypoxia suppresses T cell function by suppressing immune effector gene expression. HIF-1α
interacts with histone deacetylase 1 and, in conjunction with polycomb repressive complex 2, induces
chromatin remolding that epigenetically silences effector genes, leading to immune dysfunction. Targeting
HIF-1α and its associated epigenetic signaling has the potential to restore T cell function and overcome
resistance to PD-1 therapy .
[90]
Regulation mechanisms of hypoxia in immune escape
Expression of various immune checkpoint proteins is a key mechanism through which carcinoma cells
realize immune escape. These checkpoints have emerged as important targets for cancer therapy, with
PD-L1/PD-1 representing the primary negative mediators that inhibit the anticancer activity of effector T
cells. However, the therapeutic efficacy of PD-L1/PD-1 blockade has been limited, with response rates of
only approximately 10%-30% [91,92] . Hypoxia upregulates PD-L1 expression on both carcinoma and stromal
cells, while its receptors PD-1, CTLA-4, and LAG-3 are expressed on immune cells . Binding of PD-L1 to
[93]
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