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Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63 Page 750

infiltration and increase regulatory T cell (Treg) differentiation from precursor CD4+ T cells . Tregs
[10]
release suppressive cytokines such as interleukin-10 (IL-10) and TGF-β that inhibit CD8+ T cell function
and enhance cancer cell escape from the immune attack . In some solid tumors, such as pancreatic ductal
[11]
adenocarcinoma (PDAC), increased IL-10 is correlated with reduced survival [12-14] .

MDSCs are considered immature myeloid cells and secrete reactive oxygen species (ROS), IL-10, IL-13,
TGF-β, arginase-I, inducible nitric oxide synthase (iNOS), and other immunosuppressive factors [15-17] .

The TME is usually hypoxic due to a poorly developed tumor vasculature. Most cytotoxic immune cells
(CD8+ T cells and NK cells) function poorly in hypoxic states, while suppressive cells (M2 TAMs and
Tregs) thrive . The hypoxic TME favors the production of ADO and the induction of immunosuppressive
[18]
A2A receptors (A2AR) and A2B receptors (A2BR) in immune cells. A shift in tumor metabolism from
oxidative phosphorylation to primarily glycolysis also suppresses immune cell infiltration due to increased
lactate in the TME. The increase in lactate lowers tumor pH . This decrease in pH drives M2 polarization
[19]
while inhibiting the nuclear factor of activated T cells (NFAT) within T cells [20,21] . This suppression of NFAT
inhibits chemotaxis into tumors and reduces T cell activation.

The role of immune checkpoint inhibitors (ICIs) in cancer immunotherapy
Immune checkpoint inhibitors (ICIs) have greatly advanced immunotherapy, especially in some hard-to-
treat tumors. The two most studied checkpoints are CTLA4 and PD-1 [1,22,23] . Although antibodies that block
these inhibitory signals have improved survival, most patients with solid tumors eventually develop either
primary or secondary resistance to ICI. In primary resistance, tumors display early resistance to ICI and
progress soon (within six months) after ICI treatment. In secondary resistance, patients respond to
treatment initially but develop resistance later . Studies have demonstrated that the tumor mutational
[1]
burden (TMB) influences the response to ICI [24-26] . Reduced TMB within tumors treated with ICI can result
in acquired resistance to ICI immunotherapy.

Contributions to therapy resistance by suppressive state and hypoxia
Suppressive immune cells within the TME contribute to checkpoint inhibitor resistance. Tregs, MDSCs, and
M2-TAMs secrete immunosuppressive cytokines (TGF-β, CXCL8, CCL5, and IL-10) that prevent cytotoxic
infiltrating immune cells from entering the tumor [27-31] . An increase in VEGF due to the activation of the
mitogen-activated protein kinase (MAPK) pathway can also stimulate tumor angiogenesis [27-31] and inhibit
immune cell infiltration .
[32]
Hypoxia results from various physiological and pathological conditions, including solid tumors, ischemia-
reperfusion injury, stroke, and chronic obstructive pulmonary disease (COPD) . A hypoxic TME
[33]
contributes to an increase in extracellular ADO. The molecular mechanisms underlying hypoxia-driven
responses include Adora2a and Adora2b via HIF-1α and HIF-2α [34,35] . HIFs also stimulate angiogenesis,
vasodilation, and attenuation of inflammation [34,36] . HIF-1α induces CD73 and CD39 and increases the
conversion of ATP into ADO, leading to T cell inhibition, metastasis, and increased angiogenesis [37-40] . The
accumulation of ADO within tumor suppresses cytotoxic immune cells and APCs, such as CD8+ T cells and
DCs, while enhancing the accumulation of immunosuppressive cells [41,42] . When ADO encounters its
receptors, it can affect the activity of neutrophils and macrophages, reducing the release of IL-12, tumor
necrosis factor-alpha (TNFα), and ROS [43-45] .

The role of cancer-associated fibroblasts (CAFs) in tumor development
Cancer-associated fibroblasts (CAFs) have a different morphology than other cells within the tumor. They
lack epithelial, endothelial, and leukocyte markers, and do not have the same mutations as tumor cells .
[46]