Fig. 3. Diversity and spatial distribution of tissue immunity may underlie the resistance to disseminated tumour cell outgrowth at infrequent sites of metastases.

a, In the thyroid, the continuous production and high concentration of thyroid hormones (such as tri-iodothyronine, thyroxine and calcitonin) maintains natural killer (NK) cell, T cell and NKT cell activity, stimulates the maturation and antigen presentation capacity of dendritic cells (DCs), and sparks monocyte phagocytic activity. It is plausible that this naturally hyperactive local immunosurveillance maintains dormancy of disseminated tumour cells (DTCs) and antagonizes metastatic outgrowth at this site. b, Beyond their high numbers, splenic immune cells display an intricate positioning within the three main structures of the spleen: the inner white pulp (WP), where cytokine-mediated compartmentalization separates T cell and B cell areas into distinct zones; the red pulp (RP), which harbours many immune cells with innate immune functions that selectively express distinct pattern recognition receptors, helping to tailor the nature of both the early innate immune response and the subsequent adaptive immune response; and the in-between marginal zone, harbouring concentric macrophage subsets and DCs with defined positioning to ensure efficient pathogen encounter and antigen presentation. It is possible that this sharp anatomical parsing of immunosurveillance readies the splenic antimetastatic niche by facilitating low-probability DTC–immune cell interactions. Although these hypotheses are enticing, specific mechanisms driving immune-mediated low frequency of metastases in the thyroid and spleen remain to be seen.