Acid-Base Modulation in Cancer: From Mechanism to Therapy

The field of tumor microenvironment (TME) research has unveiled the crucial influence of acid–base dynamics in shaping cancer progression, metastatic behavior, immune evasion, and resistance to conventional therapies. A hallmark of solid tumors is the aberrant establishment of an inverted pH gradient -where tumor cells maintain an elevated intracellular pH and an acidic extracellular environment- largely due to metabolic reprogramming, such as aerobic glycolysis and upregulation of proton transporters including NHE1, V-ATPase, and MCTs. This disturbed proton homeostasis fosters genomic instability, epithelial–mesenchymal transition, heightened proteolytic activity, and compromised anti-tumor immune responses. Recent studies have reinforced the central role of extracellular acidosis in hindering the efficacy of chemotherapies, radiotherapy, targeted therapies, and immune checkpoint inhibitors, representing an urgent challenge in oncology. While modulation of tumor pH has gained attention, the precise mechanisms and translational strategies remain active areas of investigation.This Research Topic aims to consolidate basic, preclinical, and clinical advances in alkalization therapy with the goal of reprogramming the cancer microenvironment to suppress malignancy and potentiate therapeutic response. The core objective is to elucidate how therapeutic strategies that raise extracellular pH -such as dietary interventions, buffering agents, proton pump inhibitors, and pH-responsive nanomedicines- can remodel intracellular signaling, metabolic flux, and immunological function. By integrating multidisciplinary expertise, we seek to identify innovative biomarkers, unravel novel regulatory circuits in proton dynamics, and determine the translational potential of combining alkalization therapy with existing cancer treatments, particularly for tumors characterized by high acid production and resistance to immune attack.This Research Topic welcomes contributions spanning molecular, metabolic, immunological, and clinical perspectives. Contributions may include mechanistic explorations, translational studies, clinical trials, and theoretical modeling. Areas of focus are limited to interventions and consequences of pH modulation in human and experimental tumor systems. To gather further insights in this evolving area, we welcome articles addressing, but not limited to, the following themes:- pH-dependent regulation of tumor cell signaling and metabolism- Molecular mechanisms and regulation of proton transport systems- Systems biology and thermodynamic modeling of pH homeostasis- Development and validation of pH-based biomarkers- Buffering strategies, dietary or pharmacological, for pH modulation- pH-responsive nanomedicine for targeted therapy- Integration of alkalization with immunotherapy and chemotherapy- Clinical outcomes and cohort analyses of alkalization interventionsDr. Hiromi Wada declares that they're affiliated with Karasuma Wada Clinic. The other Topic Editors declare no competing interests with regard to the Research Topic subject. Topic editors: Hiromi Wada, Dario Marchetti, Zeina Dassouki Source: https://www.frontiersin.org/research-topics/76789/acid-base-modulation-in-cancer-from-mechanism-to-therapy