🔷Tumors exploit metabolic pathways to create an immunosuppressive microenvironment that allows them to evade immune surveillance and thrive. Changes in tumor metabolism, including glycolysis, lipid metabolism, and amino acid utilization, can significantly affect immune cell function within the tumor microenvironment (TME).

🔷A key metabolic change is the Warburg effect, whereby tumor cells favor glycolysis and produce high levels of lactate even in the presence of oxygen. This acidifies the TME, thereby impairing the function of cytotoxic T cells and natural killer (NK) cells while promoting regulatory T cell (Treg) proliferation. In addition, tumor cells consume essential nutrients such as glucose and glutamine at high rates, starving immune cells of the energy required for activation and effector functions.

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☑️Lipid metabolism also plays a crucial role in immune evasion. Tumor cells accumulate fatty acids and cholesterol, which aid their survival and proliferation. At the same time, lipid overload in dendritic cells (DCs) impairs their antigen-presenting capacity, thereby reducing T cell activation. Additionally, tumor-induced upregulation of enzymes such as indoleamine 2,3-dioxygenase (IDO) depletes tryptophan, an amino acid critical for T cell proliferation, resulting in immunosuppression.

Hypoxia in the tumor microenvironment (TME) plays a significant role in immune evasion by creating an immunosuppressive milieu. Under low oxygen conditions, tumor cells stabilize hypoxia-inducible factor 1-alpha (HIF-1a), a key transcription factor that regulates the cellular response to hypoxia. HIF-1a activation leads to the upregulation of various genes involved in angiogenesis, metabolism, and immune modulation, including immunosuppressive cytokines like vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-β).

VEGF promotes the formation of abnormal blood vessels, which not only impedes efficient immune cell infiltration into the tumor but also supports tumor growth by providing nutrients and oxygen. Additionally, VEGF can inhibit the function of effector immune cells like cytotoxic T lymphocytes (C toxic T nd natural killer immune cells like cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, further dampening the immune response.

TGF-B, on the other hand, is a potent immunosuppressive cytokine that can impair the activation and function of immune cells. It can induce the differentiation of regulatory T cells (Tregs), which suppress the activity of effector immune cells, and also promote the expansion of myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous population of immune cells that can further contribute to immune suppression by inhibiting the activity of T cells and NK cells within the TME.

TAMs are often polarized to an M2-like phenotype within the TME, leading to immune evasion. M2-TAMs secrete VEGF, IL-10, and other factors that inhibit T cell function, promote angiogenesis, and support tumor progression. Their recruitment is mediated by tumor-secreted factors such as CSF-1 and CCL2.

The cumulative effect of these immunosuppressive cells is to suppress antitumor immune responses, allowing tumors to grow uncontrollably. Targeting the recruitment and function of these cells is a promising strategy in cancer immunotherapy. Approaches include inhibiting chemokine pathways (e.g., CCR5, CCL2), reprogramming TAMs to an M1-like phenotype, or depleting Tregs and MDSCs to restore immune activity. By neutralizing the immunosuppressive influence of these cells, the TME can be reprogrammed to enhance the efficacy of immune checkpoint inhibitors and adoptive cell therapy.