Natural products targeting the metabolic-immune microenvironment to overcome therapeutic resistance in castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) remains difficult to control because treatment selects adaptive tumour states beyond androgen receptor reactivation. Metabolic rewiring, stromal support, redox adaptation, ferroptosis escape and immune suppression form an interconnected resistance ecosystem that can blunt androgen receptor pathway inhibitors, taxanes and immune-based therapy. The candidates reviewed span polyphenols (curcumin, stilbenoids, flavonoids and isoflavones), isothiocyanates, carotenoids, terpenoids, alkaloids and characterised botanical extracts. Reported effects span glycolysis, lactate signalling, lipid metabolism, mitochondrial function, NAD + metabolism, reactive oxygen species and ferroptosis in prostate-cancer models. Functional immune sensitisation is limited to a small subset tested in immunocompetent models; many studies report only tumour-cell markers or immune-cell abundance. Evidence from acquired or selected drug-resistant models is limited; other findings derive from CRPC models without documented selection or non-CRPC settings. This review presents evidence for selected compounds as candidate modulators of metabolic-immune resistance in CRPC. Mechanism-linked examples include curcumin in lactate-associated docetaxel tolerance, sulforaphane in lipid and glycolytic reprogramming, and Gnetin C or resveratrol in NAD + /mitochondrial stress. Other examples include QGGP and quercetin delivery in stromal or stem-like niches, lycopene in AKT/EZH2/AR signalling, and Rh2, artesunate and evodiamine in ferroptosis. Piperlongumine has been linked to immunogenic cell death and checkpoint sensitisation. Clinical and translational evidence for sulforaphane, pomegranate, curcumin and green-tea polyphenols comes mainly from non-mCRPC settings. Taxane and biomarker studies in advanced disease are considered separately. Translation requires exposure-verified, biomarker-matched combinations that connect compound pharmacology to resistant tumour state, immune-metabolic context and clinically meaningful endpoints.