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Review
. 2023 Oct 10;56(10):2206-2217.
doi: 10.1016/j.immuni.2023.07.018. Epub 2023 Sep 12.

Targeting innate immune pathways for cancer immunotherapy

Longyue L Cao  1 , Jonathan C Kagan  2
Affiliations
Review

Targeting innate immune pathways for cancer immunotherapy

Longyue L Cao et al. Immunity. .

Abstract

The innate immune system is critical for inducing durable and protective T cell responses to infection and has been increasingly recognized as a target for cancer immunotherapy. In this review, we present a framework wherein distinct innate immune signaling pathways activate five key dendritic cell activities that are important for T cell-mediated immunity. We discuss molecular pathways that can agonize these activities and highlight that no single pathway can agonize all activities needed for durable immunity. The immunological distinctions between innate immunotherapy administration to the tumor microenvironment versus administration via vaccination are examined, with particular focus on the strategies that enhance dendritic cell migration, interferon expression, and interleukin-1 family cytokine production. In this context, we argue for the importance of appreciating necessity vs. sufficiency when considering the impact of innate immune signaling in inflammation and protective immunity and offer a conceptual guideline for the development of efficacious cancer immunotherapies.

Keywords: IL-1; STING; TLRs; Toll-like receptors; anti-tumor immunity; cGAS; cancer vaccines; dendritic cells; inflammasomes; innate immunity; pattern recognition receptors.

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Conflict of interest statement

Declaration of interests J.C.K. consults and holds equity in Corner Therapeutics, Larkspur Biosciences, and Neumora Therapeutics. J.C.K. is listed as an inventor on patents filed by Boston Children’s Hospital on the use of novel dendritic cell stimuli in a therapeutic setting. None of these relationships influenced this study.

Figures

Figure 1.
Figure 1.. Five key activities in DCs that are needed to stimulate new and long-lived antigen-specific T cell responses.
A generalized, color-coded depiction of these key activities (antigen presentation, co-stimulation, immunostimulatory cytokine production, IL-1 production, cell migration) is provided at the center of the figure and elaborated at the periphery.
Figure 2.
Figure 2.. The effect of various innate immune stimuli on the key DC activities.
Relative capacity for different innate immune agonists (TLR, cGAS, with and without adjuvants aluminum hydroxide (alum) or PGPC) to stimulate the key DC activities that are important for eliciting optimal T cell mediated immunity. We note that not all innate immune agonists are shown (e.g. ligands for CLRs) and not all have been examined in the same studies. As such, the relative intensity of innate immune activities depicted should be considered speculative and may be context dependent.
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