Nanoparticle-based strategies for immune modulation and reorganization in the tumor microenvironment to combat cancer...

The tumor microenvironment (TME) is a complex ecosystem that weakens the effectiveness of cancer treatments, especially immunotherapy. Characterized by hypoxia, extracellular acidosis, aberrant enzyme activity, dense extracellular matrix (ECM), and an abundance of immunosuppressive cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), the TME creates formidable barriers to drug delivery and immune activation. Nanoparticles (NPs) have become adaptable tools for addressing these issues by facilitating accurate targeting and reprogramming of immune cells while concurrently restructuring the TME. Engineered NPs can deliver immunomodulators directly to TAMs, dendritic cells, or T cells, reversing immune exhaustion and promoting anti-tumor responses. Beyond immune cell engagement, NPs are increasingly designed to respond to or correct pathological TME cues: hypoxia-activated or oxygen-generating NPs alleviate oxygen deprivation and reduce hypoxia-inducible factor 1-alpha (HIF-1α)-driven immunosuppression; pH-sensitive carriers exploit extracellular acidosis for tumor-selective drug release; enzyme-responsive systems enhance penetration and specificity; and co-delivery of ECM-degrading enzymes improves NP diffusion and T-cell infiltration. Moreover, multifunctional nanoplatforms integrating immune activation with TME normalization, such as simultaneous TAM repolarization, vascular normalization, and checkpoint blockade, demonstrate synergistic efficacy. This review comprehensively examines how nanotechnology bridges the gap between TME biology and therapeutic intervention, highlighting advances in NP design, mechanistic insights into TME remodeling, and emerging clinical translation.