Tumor microenvironment-adaptive nanocatalysts: harnessing pH gradients for selective and synergistic cancer therapy

Malignant tumors represent a major threat to human health, underscoring an urgent need for the development of innovative therapeutic strategies. Tumor catalytic therapy has emerged as a promising approach that leverages the acidic tumor microenvironment (TME) and the rational design of pH-responsive catalytic nanomaterials to achieve safe and effective cancer treatment. This review summarizes the acidic characteristics of the TME and the design and synthesis strategies of pH-responsive nanocatalysts. These materials remain inert under normal physiological conditions (pH ≈ 7.4) but are specifically activated within the acidic TME (pH < 6.5), enabling the in situ generation of antitumor agents. Mechanistically, these nanocatalysts catalyze the production of cytotoxic species within the acidic TME, thereby inducing apoptosis or necrosis in tumor cells with high selectivity. This review further discusses the therapeutic potential of these platforms, including their integration with other treatment modalities, strategies to enhance therapeutic efficacy, and current methods for evaluating bio-compatibility and bio-safety. Key challenges are also addressed, such as material stability, tumor heterogeneity, and bio-safety concerns. Finally, future research directions are proposed, emphasizing the need for optimized material design to improve treatment efficiency and minimize side effects. Notably, this review introduces a mechanism-based classification framework and traces the evolutionary trajectory of the field from passive pH-responsive systems to self-amplifying cascades and intelligent feedback-controlled platforms, offering a distinctive perspective that differentiates it from existing literature. In summary, pH-responsive tumor catalytic therapy represents a highly promising paradigm for cancer treatment, and this review serves as a comprehensive reference to guide further progress in this field.