Metal-phenolic networks: a promising strategy for cancer immunotherapy

Cancer immunotherapy has revolutionized oncology, yet its clinical efficacy remains constrained by the immunosuppressive tumor microenvironment, poor immune cell infiltration, low tumor immunogenicity, and inefficient delivery of immunomodulators. Metal-phenolic networks (MPNs), coordination assemblies formed from polyphenolic ligands and metal ions, have attracted increasing interest for their dual role in integrating material-intrinsic immune modulation with drug delivery. Metal ions such as Mn²⁺ and Fe²⁺ mediate context‑dependent immune regulation. Mn²⁺ boosts cGAS‑STING activation by enhancing dsDNA sensing and cGAMP‑STING interactions, while Fe²⁺ induces immunogenic cell death through Fenton reactions, with activities governed by factors including metal dose and redox state. Meanwhile, polyphenolic ligands provide structural scaffolding, interfacial assembly capability, cargo-loading capacity, and complementary bioactivity. The dynamic coordination bonds of MPNs further confer responsiveness to pH, glutathione, reactive oxygen species, ATP, and external stimuli, thereby enabling controlled payload release within tumors. This review critically summarizes the composition, assembly mechanisms, functionalization strategies, and stimuli-responsive properties of MPNs, with a particular focus on their applications in cancer immunotherapy encompassing immunotherapeutic agent delivery, intrinsic immunomodulation, combination therapy, and diagnostic imaging. We also examine major current limitations, including batch-to-batch reproducibility, pharmacokinetic uncertainty, metal-associated toxicity, premature disassembly, and the predominance of preclinical evidence. Overall, MPNs represent a promising class of coordination-based biomaterials for mechanistically informed cancer immunotherapy, but progress toward clinical translation will require clearer structure-activity relationships, reproducible manufacturing, clinically relevant in vivo validation, and long-term safety assessment.