Remodeling the fortress: phytochemical-loaded nanocarriers to disrupt the therapy-resistant lung tumor...

Lung cancer remains a leading cause of cancer-related mortality worldwide, and its clinical management is profoundly hampered by the development of therapy resistance. This resistance is largely orchestrated by the dynamic and complex tumor microenvironment (TME), which functions as a collaborative "fortress" that promotes immune evasion and treatment failure. Phytochemicals, natural bioactive compounds from plants, represent a potent, multi-targeted therapeutic armory capable of simultaneously disrupting various components of the TME (e.g., cancer-associated fibroblasts, immunosuppressive cells, and hypoxic signaling). However, their clinical translation is severely limited by poor pharmacokinetic properties, including low solubility and bioavailability. This review articulates a convergent strategy to overcome this impasse, proposing the use of sophisticated nanocarrier systems for the targeted delivery of phytochemicals. We argue that the synergy between the multi-pronged biological activity of phytochemicals and the enhanced delivery, stability, and targeting afforded by nanotechnology is essential for effective TME remodeling. This review systematically deconstructs the mechanisms of therapy resistance within the lung TME, details how specific phytochemicals counteract these mechanisms, and explains the engineering principles behind advanced nanocarriers, including lipid-based, polymeric, and inorganic systems. We further consolidate compellingin vivoevidence demonstrating the efficacy of these phytochemical-loaded nanocarriers in modulating the TME and enhancing therapeutic outcomes. Finally, we discuss the major translational hurdles, such as standardization, protein corona formation, and scalable manufacturing, and outline future perspectives, including smart TME-responsive nanosystems and combinatorial regimens. This convergent strategy represents a promising path toward dismantling the therapy-resistant fortress of lung cancer.