Nano-engineered phytochemicals in cancer therapy: mechanistic insights into apoptosis, ferroptosis, tumor microenvironment modulation and drug resistance reversal

Cancer progression and therapeutic resistance are driven by interconnected mechanisms involving redox imbalance, metabolic plasticity, epigenetic remodeling and tumor microenvironment (TME)-mediated immune suppression. Conventional “one drug-one target” therapies often fail to overcome these adaptive oncogenic networks, resulting in multidrug resistance and disease relapse. This review aims to explore the therapeutic potential of nano-engineered phytochemicals in cancer management, with emphasis on ferroptosis induction, oncogenic pathway modulation and TME reprogramming for overcoming tumor resistance. A comprehensive narrative review was conducted focusing on recent advances in nano-phytomedicine, ferroptosis-based anticancer strategies and precision nanotherapeutic approaches. Relevant literature was systematically collected from PubMed, Scopus, ScienceDirect and Web of Science databases, considering both preclinical and clinical studies. Retrieved studies were critically analyzed to evaluate the therapeutic effects of nano-engineered phytochemicals on major oncogenic signaling pathways, including PI3K/Akt, NF-κB, STAT3, HIF-1α and NRF2. Mechanistic evidence associated with ferroptosis induction, reactive oxygen species (ROS) modulation, oxidative stress regulation, immune reprogramming and tumor microenvironment (TME) remodeling was systematically assessed. Preclinical studies indicate that nano-engineered phytochemicals can modulate interconnected oncogenic, metabolic, redox and immune pathways and can improve physicochemical and pharmacokinetic properties relative to free phytochemicals. Ferroptosis-associated effects include modulation of glutathione metabolism, GPX4, SLC7A11, iron homeostasis and lipid peroxidation; however, these molecular changes do not independently establish ferroptotic cell death. Evidence for tumour-microenvironment modulation and multidrug-resistance reversal remains predominantly preclinical, whereas human studies are limited and mainly address pharmacokinetic, tolerability or early efficacy outcomes. Nano-engineered phytochemicals represent a promising systems-oriented therapeutic strategy, but their clinical potential remains incompletely established. Future development requires rigorous mechanistic validation, reproducible formulation and manufacturing processes, biomarker-guided clinical evaluation, and comprehensive assessment of biodistribution, toxicity and long-term safety. (Figure presented.) Clinical trial: The manuscript is a review article (not a part of Clinical trial), hence no Clinical trial no is applicable.