The role of the immune tumor microenvironment in shaping metastatic dissemination, dormancy, and outgrowth

Abstract

The tumor microenvironment (TME) is a dynamic and complex ecosystem composed of cancer cells and diverse non-malignant cell types, including immune cells, fibroblasts, and endothelial cells. Once viewed as passive bystanders, these host cells are now recognized as active participants in tumor progression, especially during metastasis. The TME varies by organ, cancer type, and disease stage, and shapes the trajectory of cancer progression. Among the immune cells in the TME, macrophages, neutrophils, and T cells play especially crucial and context-dependent roles - either promoting or inhibiting metastatic spread depending on the tumor stage, immune cell phenotypic states, and interactions. In this review we focus on the multifaceted contributions of these key immune populations across the major stages of the metastatic cascade: initiation, survival in the circulation, dissemination, dormancy, and reactivation. These insights highlight the heterogeneity of the metastatic immune microenvironment and underscore the therapeutic potential of targeting macrophages, neutrophils, and T cells to combat metastatic disease.

Keywords: circulating tumor cells (CTCs); disseminated tumor cells (DTCs); dormancy; immune tumor microenvironment; metastasis.