Coupling redox regulation with Cancer immunotherapy: The challenge of polyphenol Nanocarriers

Cancer progression is closely associated with dysregulated redox homeostasis within the tumour microenvironment (TME), where reactive oxygen and nitrogen species influence tumour survival, immune evasion, and therapeutic resistance. While physiological redox signalling supports antitumour immunity, persistent oxidative stress promotes immunosuppression and limits the efficacy of immunotherapies, making redox modulation an attractive therapeutic strategy. Naturally occurring polyphenols have emerged as promising redox-regulating agents due to their antioxidant, anti-inflammatory, and immunomodulatory properties. Beyond scavenging reactive species, they regulate pathways involved in immune activation, metabolic reprogramming, ferroptosis, and tumour-immune interactions. However, their clinical application is hindered by poor bioavailability, rapid metabolism, and limited tumour accumulation. Nanotechnology-based delivery systems, including liposomes, polymeric nanoparticles, metal-based nanoplatforms, biomimetic vesicles, and stimuli-responsive carriers, have been developed to overcome these limitations. These platforms enhance polyphenol stability, targeted delivery, and controlled release while enabling synergistic interactions with immunotherapy. Importantly, they can function as programmable redox-immunomodulatory systems capable of remodelling the TME, inducing immunogenic cell death, promoting ferroptosis, and activating innate and adaptive immune responses. This review discusses the interplay between redox regulation and tumour immunity, examines the immunomodulatory mechanisms of polyphenols, and highlights recent advances in nanocarrier-based delivery strategies. Challenges related to biological heterogeneity, biomarker development, manufacturing scalability, regulatory approval, and clinical translation are also considered, together with future perspectives for precision redox medicine based on polyphenol-enabled nanotechnologies.