Figure 2.

Lactic acid buildup in the TME impacting immunological pathways resulting in impaired T-cell anti-tumour response. Hypoxia in the tumour core, over-consumption of glucose, and increased expression of LDH and lactate transporters contribute to the TME acidification. Increased acidity in the TME hampers the function of TILs by multiple mechanisms - inhibiting energy metabolism, upregulating inhibitory receptors (e.g., PD-1), disrupting TCR signalling, and producing immunosuppressive cytokines, enzymes, and signalling proteins (e.g., IL-4, IL-10, CCL5, TGFβ, VEGF). It also inhibits the ability of DCs to prime Th1 cells and skews TAM polarization toward the M2 phenotype. These M2-like TAMs lack the ability of phagocytizing tumour cells and help tumour cells escape from the TIL attack.