Symbiotic cancer cell-stroma crosstalk in the acidic tumor microenvironment

The acidic microenvironment (AME) is a defining metabolic feature of solid tumors that fundamentally reshapes tumor-stroma interactions. Tumor acidosis arises from multiple metabolic processes, including hypoxia-driven glycolysis in poorly vascularized regions, the Warburg Effect (WE) in well-perfused areas, and carbon dioxide accumulation from tumor respiration. As a sustained ecological stress distinct from physiological pH (∼7.4), extracellular acidosis imposes powerful selective pressures within the tumor ecosystem. In response, cancer and stromal cells must adapt through selection of pre-existing phenotypic heterogeneity or acclimate through phenotypic plasticity that enables rapid, non-genetic state transitions. AME influences all stromal components, including fibroblasts, macrophages, extracellular matrix proteins such as collagen and fibronectin, and the broader metabolic habitat, thereby remodeling the tumor niche. Through these adaptive processes, acidosis drives stromal reactivity, niche construction, and reciprocal crosstalk that promote tumor growth, invasion, and metastasis. This review highlights AME as an ecological force governing cancer-stroma symbiosis and proposes mathematical modeling as a systems-level tool to dissect the dynamic and nonlinear interactions that shape the tumor ecosystem and evolution.