The Role of the Innate Immune System in Cancer Dormancy and Relapse

SIMPLE SUMMARY: Overall survival of patients with cancer is dependent on the success of therapy. Therapy failure is correlated with enhanced metastasis and recurrence of the primary tumor. However, metastases may develop before the detection of a primary tumor and become dormant at their secondary site, presenting a major clinical challenge as these dormant cells can reactivate after the completion of seemingly successful therapy. Research has demonstrated that the innate immune system plays an integral role in molecular crosstalk with cancer cells to facilitate metastatic dissemination and control over a dormant cell state. Here, we discuss which types of innate immune cells are engaged in this crosstalk at each stage of the metastatic cascade. We also highlight how different subtypes of innate immune cells induce dormancy in cancer cells and facilitate the emergence from a dormant state. Lastly, we examine current therapeutic strategies aimed at inhibiting immune-mediated metastasis and dormancy. ABSTRACT: Metastatic spread and recurrence are intimately linked to therapy failure, which remains an overarching clinical challenge for patients with cancer. Cancer cells often disseminate early in the disease process and can remain dormant for years or decades before re-emerging as metastatic disease, often after successful treatment. The interactions of dormant cancer cells and their metastatic niche, comprised of various stromal and immune cells, can determine the length of time that cancer cells remain dormant, as well as when they reactivate. New studies are defining how innate immune cells in the primary tumor may be corrupted to help facilitate many aspects of dissemination and re-emergence from a dormant state. Although the scientific literature has partially shed light on the drivers of immune escape in cancer, the specific mechanisms regulating metastasis and dormancy in the context of anti-tumor immunity are still mostly unknown. This review follows the journey of metastatic cells from dissemination to dormancy and the onset of metastatic outgrowth and recurrent tumor development, with emphasis on the role of the innate immune system. To this end, further research identifying how immune cells interact with cancer cells at each step of cancer progression will pave the way for new therapies that target the reactivation of dormant cancer cells into recurrent, metastatic cancers.