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Page 749 Remley et al. Cancer Drug Resist 2023;6:748-67 https://dx.doi.org/10.20517/cdr.2023.63

induce T cell exhaustion, effectively escaping immune surveillance. These mechanisms allow some tumors
to grow unchecked and resist conventional cancer therapies.

Checkpoint inhibitors that block immunosuppressive signaling molecules such as PD-1, T lymphocyte
antigen 4 (CTLA4), and lymphocytic activation gene 3 protein (LAG-3) have ushered in a new era of cancer
immunotherapy, offering hope for prolonged survival and enhanced quality of life for many patients.
However, the beneficial effects of these therapies are not universal due to the ability of some tumors to
maintain an immunosuppressive environment. The interplay between cancer cells and immune cells within
the tumor microenvironment (TME) is a critical determinant of the therapeutic response.

A key driver of immunosuppression within the TME is extracellular adenosine (ADO), an adenosine
triphosphate (ATP) metabolite. ADO formation and its immunosuppressive signaling play a pivotal role in
maintaining the immunosuppressive state of the TME, promoting tumor growth, and facilitating resistance
to other therapies. This review explores the role of ADO signaling in the TME. Inhibiting ADO receptors on
immune cells reduces immunosuppression and, in some cases, has an additive antitumor effect when
combined with other cancer treatments.

UNDERSTANDING NON-RESPONDERS TO IMMUNOTHERAPY IN SOLID TUMORS
Despite having antitumor effects, cancer immunotherapy often fails. One prominent reason is that most
tumor proteins are recognized as self-proteins and fail to activate T cells, which serve as the frontline
warriors of the adaptive immune response . To the extent that tumors are recognized by the immune
[1]
system, their activation is muted by immunosuppressive signals like adenosine.

Antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs) also regulate the immune
response to tumors . The function of APC is to recognize, engulf, and present tumor antigens on their
[2]
surface. Their failure to optimally phagocytose and present antigens can undermine the initiation of
adaptive immunity. The host’s baseline immune response also significantly influences the success or failure
of cancer immunotherapy. The baseline immune response is crucial in determining treatment efficacy,
represented by the association between increased T cell infiltration into tumors and improved patient
survival and immunotherapy response rates . However, the factors that dictate the extent of T cell
[3]
infiltration into tumors, whereby an extensively infiltrated tumor is considered “hot”, and a sparsely
infiltrated tumor is considered “cold”, are just beginning to be elucidated. The factors that influence
infiltration vary across tumor types and subtypes due to immune cell heterogeneity . The complexity and
[4]
dynamics of the immune system, in conjunction with the adaptability of tumor cells, create a challenging
landscape for the successful deployment of cancer immunotherapy.

The complexity of the TME in solid tumors
The TME in solid tumors is complex, consisting of various immune cells, cytokines, chemokines, and
metabolites. Specific features of the TME depend on the tumor type and the location within the patient.
Some tumors develop an extracellular matrix (ECM) of fibrous proteins and stromal cells that define and
isolate the TME from the surrounding tissue . Within “cold” solid tumors, very few antitumor CD8+ T
[5,6]
cells, NK cells, and DCs are present, due to failure by immune cells to enter through the ECM . Immune
[7]
cells that contribute to the immunosuppressive state are tumor-associated macrophages (TAMs) and
myeloid-derived suppressor cells (MDSCs). Monocytes that enter tumors can polarize into M1
(proinflammatory) or M2 (immuno-suppressive) cells. In cancer, most become M2 and MDSC and
[8]
function to secrete vascular endothelial growth factor (VEGF) and transforming growth factor β (TGF-β),
which stimulates angiogenesis within the tumor . M2-TAMs and MDSCs also suppress CD8+ T cell
[9]