Tumor microenvironment conversion through intelligent nanomedicine: a paradigm shift in overcoming chemoresistance

Chemoresistance remains a major challenge in effective cancer management, significantly limiting the therapeutic efficacy of conventional chemotherapy and contributing to tumor recurrence, metastasis, and poor clinical outcomes. Increasing evidence highlights the pivotal role of the tumor microenvironment (TME) in driving therapeutic resistance through complex biological and physicochemical barriers, including hypoxia, acidic pH, abnormal vasculature, elevated interstitial fluid pressure, immune suppression, and dense extracellular matrix deposition. These TME-associated factors collectively impair drug penetration, promote tumor survival, and reduce chemosensitivity. Consequently, contemporary anticancer strategies are shifting from direct tumor cell eradication toward dynamic modulation and conversion of the TME. In this context, intelligent nanomedicine has emerged as a transformative platform capable of precisely responding to endogenous and exogenous stimuli such as pH, redox gradients, hypoxia, enzymes, light, and magnetic fields for site-specific drug delivery and controlled therapeutic activation. Stimuli-responsive nanocarriers not only enhance intratumoral drug accumulation and penetration but also actively remodel the TME through immunomodulation, vascular normalization, extracellular matrix degradation, photodynamic and photothermal effects, and catalytic reactive oxygen species generation. Such multifunctional nanosystems can effectively reverse chemoresistance by reprogramming the tumor milieu into a therapeutically responsive state. This review comprehensively discusses recent advances in intelligent nanomedicine-mediated TME conversion strategies, their mechanistic role in overcoming chemoresistance, and their translational potential in precision oncology. Collectively, TME-targeted intelligent nanomedicine represents a paradigm shift in cancer therapeutics, offering new opportunities for improving therapeutic efficacy while minimizing systemic toxicity.