Page 12 - Read Online

Cheng et al. Cancer Drug Resist. 2025;8:46 Page 5 of 28

Exhausted T cells, in turn, release chemokines and growth factors that recruit monocytes into the tumor and
promote their differentiation into TAMs. This establishes a self-enforcing positive feedback loop, which is
further accelerated under hypoxic conditions [72,73] . The transcription factor interferon regulatory factor-8
(IRF8), expressed by TAMs, has also been identified as a mediator of T cell exhaustion by enhancing TAM
antigen-presenting capacity .
[74]

TAMs and MDSCs reinforce each other’s activity through IL-10 secretion. MDSCs regulate Treg expansion
via IFN-γ and IL-10 , and they directly inhibit antigen-specific CD8 T cell activation by overproducing
+
[60]
reactive oxygen species (ROS) and nitrating tyrosines, thereby disrupting peptide-MHC binding .
[75]
Additionally, TAMs indirectly impair T cell function via MDSCs by promoting the conversion of ATP into
adenosine . Adenosine strongly suppresses antigen-specific T cell responses and the expression of cytotoxic
[76]
effector molecules such as Fas ligand and perforin , and it also inhibits NK cell function .
[77]
[77]
TAMs express a wide range of immune checkpoint molecules, including programmed death-ligand 1
(PD-L1), PD-L2, PD-1, signal regulatory protein α (SIRP-α), and sialic acid-binding immunoglobulin-like
lectin 10 (Siglec-10) [60,78] . Engagement of PD-1 with PD-L1 recruits Src homology 2-containing tyrosine
phosphatases to the immunoreceptor tyrosine-based switch motif, suppressing downstream signaling
pathways such as PI3K/Akt and Ras. This results in T cell arrest at the G1 phase, inhibition of proliferation,
and enhanced conversion of naïve T cells into inducible Tregs . TAMs have also been shown to promote T
[79]
cell apoptosis through PD-L1/PD-1 signaling . Furthermore, SIRP-α expressed on macrophages interacts
[52]
with cluster of differentiation 47 (CD47), which is often overexpressed on cancer cells, delivering a “don’t eat
me” signal that enables tumor immune evasion . Similarly, the Siglec-10/CD24 axis functions as another
[78]
“don’t eat me” pathway, allowing cancer cells to evade macrophage-mediated phagocytosis . A summary of
[80]
TAM-mediated mechanisms of resistance to immunotherapy is demonstrated in Figure 1.

Regulatory mechanisms of hypoxia in T cell exhaustion
Immune checkpoint inhibitors rely heavily on the activation of T cells . However, T cells exposed to
[81]
persistent antigenic stimulation in cancer gradually become dysfunctional, a state referred to as exhaustion.
Exhausted T cells are characterized by impaired effector functions, loss of memory T cell properties, and
expression of various inhibitory receptors . Hypoxia impairs the function of tumor-infiltrating lymphocytes
[82]
(TILs) by disrupting mitochondrial respiration due to low O availability. Specifically, hypoxia alters electron
2
transport within mitochondria, causing electron transfer from complex V to complex I and generating ROS,
such as superoxide, which drive TIL exhaustion . Impaired mitochondrial respiration also promotes T cell
[83]
exhaustion through HIF-1α-mediated glycolytic reprogramming [84] . In addition, the hypoxic
microenvironment triggers a transcriptional response in T cells, shifting their metabolism toward anaerobic
glycolysis, alters fatty acid metabolism, and other metabolic pathways [83,85] . Together, nutrient and oxygen
deprivation compromises T cell effector functions and exacerbates exhaustion. Chronic antigen stimulation
can activate PD-1 signaling, which contributes to CD8 T cell exhaustion. This state is associated with
+
increased lipid uptake and fatty acid oxidation . Under hypoxic conditions, the PD-1 pathway suppresses
[86]
glycolysis while promoting fatty acid oxidation in T cells, further driving exhaustion .
[87]

Hypoxia also induces ER stress by disrupting protein-folding homeostasis. This occurs because
O -dependent disulfide bond formation during posttranslational folding or isomerization in the ER is
2
impaired, leading to activation of the unfolded protein response (UPR) . Hypoxia enhances the expression
[88]
of key regulators of the UPR, including binding immunoglobulin protein (BiP) and C/EBP homologous
protein (CHOP) . Activation of the UPR promotes T cell exhaustion by increasing the expression of
[89]
immune checkpoint molecules on T cells [e.g., PD-1, TIM-3, lymphocyte activation gene 3 (LAG-3), and
cytotoxic T lymphocyte-associated antigen 4 (CTLA-4)] as well as their ligands .
[89]

5