Versatile covalent organic frameworks for cancer immunotherapy

Cancer immunotherapy has produced substantial clinical benefit, yet its efficacy remains limited in patients with immunologically "cold" tumors, which are characterized by poor T-cell infiltration and a suppressive tumor microenvironment (TME). Strategies for converting cold tumors into immunologically "hot" phenotypes include depleting or reprogramming immunosuppressive cells, modulating immunometabolism, inducing immune-stimulatory forms of cell death such as immunogenic cell death (ICD), and promoting tertiary lymphoid structure (TLS) formation to strengthen antigen presentation and T-cell recruitment. Covalent organic frameworks (COFs) are structurally programmable, porous, stable and biocompatible crystalline materials that have attracted increasing interest in biomedical research. Since the first report in 2019 that COF-mediated photodynamic therapy could induce tumor-cell apoptosis, accumulating studies have shown that multifunctional COFs can trigger immune-activating cell death, promote TLS formation and modulate immune-cell phenotypes. Versatile COFs therefore provide a promising platform for improving cancer immunotherapy. This review summarizes recent advances in COF-based immunomodulatory strategies, delineates the mechanisms by which COFs reverse tumor immunosuppression and amplify antitumor immunity, and discusses translational challenges and future directions for clinical development.