The symbiotic axis between the acidic tumor microenvironment and cancer stem cells: a driver of malignancy and therapeutic resistance

The physicochemical conditions of tumors—such as acidosis, stiffness, and hypoxia—actively drive cancer progression yet have been insufficiently incorporated into the current hallmarks of cancer model. This review focuses on one such dominant condition, the acidic tumor microenvironment (ATME), and its dynamic interplay with cancer stem cells (CSCs), proposing their cooperative interaction as a central driver of tumor aggressiveness. We present evidence that acidosis, driven by glycolytic metabolism and proton extrusion, epigenetically reprograms tumor cells toward a stem-like state through mechanisms including histone lactylation. In turn, CSCs reinforce acidity through metabolic remodeling and stromal reprogramming, forming a self-sustaining feedback loop. This ATME-CSC axis underpins key cancer hallmarks: uncontrolled self-renewal, metabolic adaptability, immune evasion, and metastasis. Disrupting this axis requires multi-target strategies that concurrently neutralize niche acidity, target CSC metabolism, and reset associated epigenetic programs. Future advances will depend on spatial mapping of this axis in vivo , development of microenvironment-responsive agents, and functional validation using patient-derived organoids. Targeting the symbiotic interface between tumor acidity and stemness offers a transformative pathway to durable therapeutic control.