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Page 751 Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63

CAF development within tumors occurs when there is an increase in inflammatory markers such as IL-6
and TGF-β due to cancer cell DNA damage [47,48] . When IL-6 and TGF-β are increased in the TME, they tend
to reduce the number of T cells, limiting the extent of the antitumor response . These cytokines increase
[49]
JAK-STAT signaling and ECM transition, promoting CAF formation [50-52] . Breast cancers increase Notch
signaling within the TME to increase CAFs . Patients who receive chemotherapy and radiation to treat
[53]
solid tumors experience DNA breaks, and this stress can promote fibrosis or CAF accumulation and
function. This change in CAF function causes resistance to therapy in various solid tumors [54-56] .

Solid tumor CAFs may exhibit different phenotypes depending on the TME. The different phenotypes
exhibit different cell surface markers, but identifying these can be challenging . Breast cancers increase
[46]
expression of fibroblast activation protein (FAP) to cause high immunosuppression through Treg
activation . Pancreatic cancers express both myofibroblastic CAFs (myCAFs) and inflammatory CAFs
[57]
(iCAFs) at different locations in the tumor. MyCAFs have high expression of TGF-β and αSMA and are
located close to tumor cells, while iCAFs have high IL-6 secretion and are more distal in the TME [58,59] .
iCAFs can recruit TAMs and MDSCs to the TME to increase the immunosuppressive state [13,60] . Targeting
the MAPK/STAT pathways in iCAFs through inhibitors in combination with checkpoint inhibitor therapy
(e.g., anti-PD-1) can lead to increased survival of patients with solid tumors like PDAC . McAndrews et al.
[60]
discovered that in early-stage PDAC, iCAFs tend to be more abundant, while myCAFs have a higher
abundance in late-stage cancer. When FAP+ CAFs were depleted, there was an increase in mouse survival.
Conversely, when αSMA+ CAFs were depleted, there was a decrease in survival. In the TME, when FAP+
CAFs were depleted, there was a decrease in macrophages and B cells. However, αSMA+ CAF loss showed a
decrease in effector T cells (Teff) and increased Tregs. A loss in IL-6 production in FAP+ CAFs increased
responses in mice to gemcitabine therapy and combination therapy of gemcitabine + checkpoint
inhibitors .
[57]
THE ADENOSINE PATHWAY: A NEW APPROACH TO OVERCOMING THERAPEUTIC
RESISTANCE TO CHECKPOINT INHIBITORS
Understanding the interaction between cells in the TME is crucial to overcoming therapeutic resistance.
The concept of targeting ADO biosynthesis or inhibiting its receptors has garnered increased interest from
the scientific community . Targeting extracellular ADO and its receptors opens opportunities for
[58]
increasing the antitumor immune response in innate and adaptive immune cell populations normally
suppressed within the TME . Since high ADO levels in the TME are predictive of immunosuppressive
[59]
responses , combining current immunotherapies with ADO blockade may help to overcome ICI resistance
[60]
in solid tumors.

Chemotherapies and various cancer treatments result in elevated cell death and heightened ATP release .
[61]
ATP is rapidly converted to ADO within solid tumors. This process is mediated by ectonucleotidases CD39
and CD73 and contributes to the formation of an immunosuppressive TME . CD39 acts on ATP to
[62]
produce adenosine monophosphate (AMP), which is subsequently converted into ADO by CD73. The
resulting extracellular ADO interacts with one of four G-protein-coupled receptors (A1R, A2AR, A2BR, and
A3R) found in tumor cells, immune cells, and endothelial cells. This increase in ADO levels within the TME
hinders the activity of effector immune cells and promotes the expansion of immunosuppressive regulatory
T cells . Exosomes released into the TME during cell death also express CD73 and CD39 .
[62]
[63]
The A2AR is associated with elevated levels of checkpoint molecules like PD-1, CTLA4, and LAG-3 on T
cells . Activation of this receptor tends to inhibit the antitumor functions of macrophages and the
[64]
proliferation and cytokine production of cytotoxic T cells . However, increased expression of CD39 and
[65]