Abstract
Cancer immunotherapy offers transformative promise particularly for the treatment of lethal cancers, since a correctly trained immune system can comprehensively orchestrate tumor clearance with no need for continued therapeutic intervention. Historically, the majority of immunotherapies have been T cell-focused and have included immune checkpoint inhibitors, chimeric antigen receptor T cells, and T-cell vaccines. Unfortunately T-cell-focused therapies have failed to achieve optimal efficacy in most solid tumors largely because of a highly immunosuppressed 'cold' or immune-excluded tumor microenvironment (TME). Recently, a rapidly growing treatment paradigm has emerged that focuses on activation of tumor-resident innate antigen-presenting cells, such as dendritic cells and macrophages, which can drive a proinflammatory immune response to remodel the TME from 'cold' or immune-excluded to 'hot'. Early strategies for TME remodeling centered on free cytokines and agonists, but these approaches have faced significant hurdles in both delivery and efficacy. Systemic toxicity from off-target inflammation is a paramount concern in these therapies. To address this critical gap, engineering approaches have provided the opportunity to add 'built-in' capabilities to cytokines, agonists, and other therapeutic agents to mediate improved delivery and efficacy. Such capabilities have included protective encapsulation to shield them from degradation, targeting to direct them with high specificity to tumors, and co-delivery strategies to harness synergistic proinflammatory pathways. Here, we review innate immune-mediated TME remodeling engineering approaches that focus on cytokines, innate immune agonists, immunogenic viruses, and cell-based methods, highlighting emerging preclinical approaches and strategies that are either being tested in clinical trials or already Food and Drug Administration approved.