1.6. Acidosis:
Acidification of the tumor microenvironment is related to metabolic adaptation and reprogramming [148]. Moreover, tumor acidosis affects metastasis, invasion, and therapeutic response and can act as a regulator of tumor progression [148]. Tumor cells have high metabolic demands that lead to the accumulation of a high amount of\(\ \)n the TME, and due to the disordered nature of tumor vasculature, effective removal of \(H^{+}\)from the extracellular environment is prevented, accordingly, the accumulation of \(H^{+}\) ions in the TME is intensified [148, 149]. Consequently, it causes hypoxic conditions and changes in glycolytic metabolism. In addition, in areas where oxidative conditions prevail, the accumulation of \(H^{+}\) causes the hydration of carbon dioxide, which meets the bioenergetic and biosynthetic needs of cancer cells, these processes happen at a high speed [148]. Low pH in TME can promote the motility of cancer cells and subsequently, influence fibroblasts and activity and polarization of macrophages by bringing about alterations in cytoskeletal dynamics [150]. In tumor regions where the lowest pH conditions prevail, the highest rate of invasion can occur and vice versa [148]. To adapt to the acidic environment, tumor cells employ all enzyme systems [106]. In general, the establishment of acidic conditions in the TME involves two events: CO2 by respiration and lactic acid formed by glycolytic metabolism [106]. Evidence shows that acidic conditions overlap both in hypoxic areas and at the tumor-stroma interface, which strongly influences tumor invasion and proliferation [151]. Moreover, according to multiple evidence, the conditions of extracellular acidosis create a suitable and beneficial environment for dormant tumor cells to support the survival of disseminated tumor cells and the formation of metastasis, and subsequently, the chemotherapy-resistant phenotype is maintained [106, 152].