Lactate oxidase-integrated nanomaterials for tumor microenvironment modulation: Mechanisms and therapeutic applications

The tumor microenvironment (TME) is dynamically remodeled by metabolic reprogramming, establishing lactate as a central orchestrator of immune evasion through acidosis, CD8⁺ T cell suppression, and epigenetic regulation. While lactate oxidase (LOX) offers therapeutic potential by converting lactate to immunomodulatory H₂O₂, its clinical translation faces critical barriers including enzymatic instability, systemic toxicity, and paradoxical pro-tumorigenic effects. To overcome these limitations, advanced LOX-integrated nanoplatforms employ two synergistic engineering strategies: stimuli-responsive carriers exploit pathological cues (pH, redox gradients, lactate concentration) for spatiotemporally controlled enzyme activation, while biomimetic modifications leverage cell membrane coatings to enhance tumor penetration and homologous targeting. These approaches collectively optimize catalytic stability, prolong intratumoral retention, and minimize off-target effects. By synchronizing lactate depletion with TME dynamics, LOX nanotherapeutics reverse immunosuppressive circuits—restoring effector T cell function, repolarizing protumoral immune cells, and synergizing with checkpoint inhibitors. The concomitant H₂O₂ generation further amplifies metal-catalyzed oxidative damage within therapeutic thresholds. Future development requires AI-optimized carrier design, scalable manufacturing, and enhanced biomimetic penetration strategies to address tumor heterogeneity. Through interdisciplinary integration of materials science and immunometabolism, LOX-based nanoplatforms represent a paradigm-shifting approach to overcoming treatment resistance by concurrently targeting metabolic dysregulation, physical barriers, and immune evasion in solid tumors.