Reprogramming the Tumor Microenvironment and Cancer Therapy via Nanocatalytic Medicine

Abstract

Abstract Cancer is one of the leading global health crises in the 21st century, accounting for nearly one in six deaths worldwide. Conventional treatment modalities, including surgery, chemotherapy, radiotherapy, and immunotherapy, remain insufficient and are frequently sabotaged due to the tumor complexity. Parallelly, there are increasing instances of both intrinsic and acquired drug resistance. The primary obstacle is the tumor microenvironment (TME), marked by hypoxia, acidosis, metabolic dysregulation, and immunosuppressive infiltration, which promotes cancer progression while protecting malignant cells from therapy and driving treatment failure. Addressing these interconnected challenges demands inventive methodologies that can simultaneously remodel the TME and dismantle resistance mechanisms. Introduction of nanocatalytic medicine (NCM) represents a transformative paradigm in oncology that utilizes enzymatic action to exploit TME aberrant physicochemical hallmarks as triggers for selective and sustained therapeutic responses. NCM allows continuous in situ TME modulation, bypassing the limitations of traditional therapies and even working effectively at low concentrations. This review examines the nanocatalytic strategies for overcoming drug resistance via catalytic hypoxia mitigation, acidosis reversal, metabolite depletion, and redox modulation utilizing TME cues for remodeling. We explore their ability to target different metabolic pathways, acting as critical mediators of drug resistance, and their emerging role in inducing the regulatory cell death pathway and/or immunogenic cell death. Nanocatalyst-directed prodrug activation and synergistic use in combination therapies that help overcome drug resistance are also discussed. Using the 4S framework (specificity, stability, safety, and scalability), we critically address design principles, biosafety, and translational challenges. Therefore, shifting the focus from evasive tumor cells toward TME modulation offers a sustainable and smart approach to refine oncological therapeutic outcomes.