Metal–Ligand Coordination Nanomaterials Tailored to the Cancer-Immunity Cycle

Conspectus The successful implementation of antitumor immunity hinges largely on a chain of stepwise events known as the cancer-immunity cycle (CIC). In this cycle, tumor cell death caused by T lymphocytes triggers inflammatory rounds of antigen-presenting cell (APC)-mediated antigen presentation and T-cell stimulation, sustaining active tumoricidal immunity, whereas tumor immunosuppressive networks impose multifaceted detrimental effects on essential elements involved in the CIC, which are considered therapeutic targets for improved tumor immunotherapy. Tremendous evidence has thrown light on the pivotal roles of metal ions in oncology, especially in antitumor immunity. Metal ions participate in modulating the step-by-step events occurring in the CIC, principally via their structural, catalytic, or modulatory interactions with immunosensors, ion transporters, and downstream effectors, as exemplified by Mn2+ that sensitizes cyclic GMP–AMP synthase and the stimulator of interferon genes pathway to trigger antitumor T-cell immunity. Owing to their lack of targeting ability, metal ions used alone cannot serve as immunotherapeutics. Inspired by the excellent targeting properties of nanomedicines and the unique ability of metal ions to self-assemble with diverse functional ligands, recent decades have witnessed rapid advances in metal–ligand coordination nanomaterials for enhanced tumor immunotherapy. Unlike other nanomedicines, metal coordination complexes can serve as multifunctional immunotherapeutic platforms, due to their chemical tunability and design versatility. Their unique composition and structure allow them to exhibit substantial outstanding properties, blazing the promising trail of tumor immunotherapy. In this Account, we summarize our recent breakthroughs in the development of metal–ligand coordination nanomedicines, especially in the therapeutic mechanisms tailored for CIC, with the ultimate purpose of ameliorative cancer immunotherapy. These promising nanomedicines are designed on the basis of stepwise events within the CIC, in which the targets can be subdivided into (1) tumor cells, (2) APCs, and (3) T cells. Once targeted to tumor cells, these nanomaterials generally induce immunogenic tumor cell death, leading to the release of numerous danger-associated molecular patterns that exert immune-stimulating effects on the APCs. Metal coordination complexes also directly activate APCs by the intrinsic immunostimulatory properties of metal ions or by delivering other adjuvants. Both pathways promote APC activation and antigen presentation for the subsequent priming of antitumor T-cell responses. Apart from indirect APC-to-T immunostimulatory pathways, these nanomedicines directly act on T cells and reinforce their antitumor functions, including activation, trafficking, infiltration, and tumor-killing capabilities. In addition, both future challenges and the anticipated development blueprint of these medicines as clinical therapeutics are emphasized.