Microvascular and stromal normalization combined with nano-immunotherapy: A synergistic strategy to overcome drug delivery barriers in solid tumors.

Solid tumors like advanced-stage prostate carcinoma pose significant hindrances to therapeutic approaches due to a rich tumor microenvironment (TME) that establishes strong physical and immune resistance to treatment. The TME is defined by a dense, fibrotic stroma and non-functional vasculature, which produce high mechanical stress, high interstitial fluid pressure (IFP), and hypoxia. These properties critically inhibit therapeutic agent penetration and suppress anti-tumor immunity. This review details the mechanistic foundation of such hindrances and discusses the nascent paradigm of TME normalization. This review critically evaluates approaches aimed at stromal normalization, which include anti-cancer stroma cell targeting and extracellular matrix (ECM) degradation, as well as vascular normalization, which involves anti-angiogenic therapy for vessel repair. The unifying hypothesis of this review is that therapeutic efficacy in advanced solid tumors can be significantly enhanced by first restoring key abnormalities of the tumor microenvironment, including vascular dysfunction and stromal stiffness, thereby improving perfusion, reducing hypoxia, and facilitating immune cell and nanoparticle penetration. This microenvironmental normalization creates a transient therapeutic window that can be strategically exploited through nano-immunotherapy. This strategy enhances the penetration of nanoparticles, streamlines immune cell migration, and counteracts immune suppression. Lastly, key clinical issues and future directions include optimal scheduling, predictive markers, and next-generation nanocarriers. This overall strategy offers a combined method to overcome cancer resistance while improving outcomes in difficult-to-treat tumors.