Cancer immunotherapy, particularly checkpoint blockade
immunotherapy (CBI), has revolutionized the treatment of some
cancers by reactivating the antitumor immunity of hosts with durable response and manageable toxicity. However, many
cancer patients with low
tumor antigen exposure and immunosuppressive tumor microenvironments do not respond to CBI. A variety of methods have been investigated to reverse immunosuppressive tumor microenvironments and turn "cold"
tumors "hot" with the goal of extending the therapeutic benefits of CBI to a broader population of
cancer patients. Immunostimulatory adjuvant treatments, such as
cancer vaccines,
photodynamic therapy (
PDT),
radiotherapy (RT),
radiotherapy-radiodynamic
therapy (RT-RDT), and chemodynamic
therapy (CDT), promote antigen presentation and T cell priming and, when used in combination with CBI, reactivate and sustain systemic antitumor immunity.
Cancer vaccines directly provide
tumor antigens, while
immunoadjuvant therapies such as
PDT, RT, RT-RDT, and CDT kill
cancer cells in an immunogenic fashion to release
tumor antigens in situ. Direct administration of
tumor antigens or indirect intratumoral
immunoadjuvant therapies as in situ
cancer vaccines initiate the immuno-oncology cycle for antitumor immune response.With the rapid growth of
cancer nanotechnology in the past two decades, a large number of nanoparticle platforms have been studied, and some nanomedicines have been translated into clinical trials. Nanomedicine provides a promising strategy to enhance the efficacy of
immunoadjuvant therapies to potentiate
cancer immunotherapy. Among these nanoparticle platforms, nanoscale
metal-organic frameworks (nMOFs) have emerged as a unique class of porous hybrid nanomaterials with
metal cluster secondary building units and organic linkers. With molecular modularity, structural tunability, intrinsic porosity, tunable stability, and biocompatibility, nMOFs are ideally suited for biomedical applications, particularly
cancer treatments.In this Account, we present recent breakthroughs in the design of nMOFs as nanocarriers for
cancer vaccine delivery and as nanosensitizers for
PDT, CDT, RT, and RT-RDT. The versatility of nMOFs allows them to be fine-tuned to effectively load
tumor antigens and
immunoadjuvants as
cancer vaccines and significantly enhance the local antitumor efficacy of
PDT, RT, RT-RDT, and CDT via generation of
reactive oxygen species (ROS) for in situ
cancer vaccination. These nMOF-based treatments are further combined with
cancer immunotherapies to elicit systemic antitumor immunity. We discuss novel strategies to enhance light tissue penetration and overcome tumor hypoxia in
PDT, to increase energy deposition and ROS diffusion in RT, to combine the advantages of
PDT and RT to enable RT-RDT, and to trigger CDT by hijacking aberrant metabolic processes in
tumors. Loading nMOFs with small-molecule drugs such as an
indoleamine 2,3-dioxygenase inhibitor, the
toll-like receptor agonist imiquimod, and biomacromolecules such as CpG
oligodeoxynucleotides and anti-CD47 antibody synergizes with nMOF-based radical
therapies to enhance their immunotherapeutic effects. Further combination with
immune checkpoint inhibitors activates systemic antitumor immune responses and elicits abscopal effects. With structural and compositional tunability, nMOFs are poised to provide a new clinically deployable nanotechnology platform to promote immunostimulatory tumor microenvironments by delivering
cancer vaccines, mediating
PDT, enhancing RT, enabling RT-RDT, and catalyzing CDT and potentiate
cancer immunotherapy.