The stimulator of interferon genes (STING) cellular signaling pathway is a promising target for cancer immunotherapy. Activation of the intracellular STING protein triggers the production of a multifaceted array of immunostimulatory molecules, which, in the proper context, can drive dendritic cell maturation, antitumor macrophage polarization, T cell priming and activation, natural killer cell activation, vascular reprogramming, and/or cancer cell death, resulting in immune-mediated tumor elimination and generation of antitumor immune memory. Accordingly, there is a significant amount of ongoing preclinical and clinical research toward further understanding the role of the STING pathway in cancer immune surveillance as well as the development of modulators of the pathway as a strategy to stimulate antitumor immunity. Yet, the efficacy of STING pathway agonists is limited by many drug delivery and pharmacological challenges. Depending on the class of STING agonist and the desired administration route, these may include poor drug stability, immunocellular toxicity, immune-related adverse events, limited tumor or lymph node targeting and/or retention, low cellular uptake and intracellular delivery, and a complex dependence on the magnitude and kinetics of STING signaling. This review provides a concise summary of the STING pathway, highlighting recent biological developments, immunological consequences, and implications for drug delivery. This review also offers a critical analysis of an expanding arsenal of chemical strategies that are being employed to enhance the efficacy, safety, and/or clinical utility of STING pathway agonists and lastly draws attention to several opportunities for therapeutic advancements.

Cancer vaccines hold promise as an immunotherapeutic modality based on their potential to generate tumor antigen-specific T cell responses and long-lived antitumor responses capable of combating metastatic disease and recurrence. However, cancer vaccines have historically failed to deliver significant therapeutic benefit in the clinic, which we maintain is due in part to drug delivery challenges that have limited vaccine immunogenicity and efficacy. In this review, we examine some of the known and putative failure mechanisms of common first-generation clinical cancer vaccines, and describe how the rational design of materials engineered for vaccine delivery and immunomodulation can address these shortcomings. First, we outline vaccine design principles for augmenting cellular immunity to tumor antigens and describe how well-engineered materials can improve vaccine efficacy, highlighting recent innovations in vaccine delivery technology that are primed for integration into neoantigen vaccine development pipelines. We also discuss the importance of sequencing, timing, and kinetics in mounting effective immune responses to cancer vaccines, and highlight examples of materials that potentiate antitumor immunity through spatiotemporal control of immunomodulation. Furthermore, we describe several engineering strategies for improving outcomes of in situ cancer vaccines, which leverage local, intratumoral delivery to stimulate systemic immunity. Finally, we highlight recent innovations leveraging nanotechnology for increasing the immunogenicity of the tumor microenvironment (TME), which is critical to enhancing tumor infiltration and function of T cells elicited in response to cancer vaccines. These immunoengineering strategies and tools complement ongoing advances in cancer vaccines as they reemerge as an important component of the immunotherapeutic armamentarium.

The tumor-associated vasculature imposes major structural and biochemical barriers to the infiltration of effector T cells and effective tumor control. Correlations between stimulator of interferon genes (STING) pathway activation and spontaneous T cell infiltration in human cancers led us to evaluate the effect of STING-activating nanoparticles (STANs), which are a polymersome-based platform for the delivery of a cyclic dinucleotide STING agonist, on the tumor vasculature and attendant effects on T cell infiltration and antitumor function. In multiple mouse tumor models, intravenous administration of STANs promoted vascular normalization, evidenced by improved vascular integrity, reduced tumor hypoxia, and increased endothelial cell expression of T cell adhesion molecules. STAN-mediated vascular reprogramming enhanced the infiltration, proliferation, and function of antitumor T cells and potentiated the response to immune checkpoint inhibitors and adoptive T cell therapy. We present STANs as a multimodal platform that activates and normalizes the tumor microenvironment to enhance T cell infiltration and function and augments responses to immunotherapy.