Subcapsular Sinus Macrophages Promote Melanoma Metastasis to the Sentinel Lymph Nodes via an IL1a–STAT3 Axis

During melanoma metastasis, tumor cells originating in the skin migrate via lymphatic vessels to the sentinel lymph node (sLN). This process facilitates tumor cell spread across the body. Here, we characterized the innate inflammatory response to melanoma in the metastatic microenvironment of the sLN. We found that macrophages located in the subcapsular sinus (SS) produced protumoral IL1a after recognition of tumoral antigens. Moreover, we confirmed that the elimination of LN macrophages or the administration of an IL1a-specific blocking antibody reduced metastatic spread. To understand the mechanism of action of IL1a in the context of the sLN microenvironment, we applied single-cell RNA sequencing to microdissected metastases obtained from animals treated with the IL1a-specific blocking antibody. Among the different pathways affected, we identified STAT3 as one of the main targets of IL1a signaling in metastatic tumor cells. Moreover, we found that the antitumoral effect of the anti-IL1a was not mediated by lymphocytes because Il1r1 knockout mice did not show significant differences in metastasis growth. Finally, we found a synergistic antimetastatic effect of the combination of IL1a blockade and STAT3 inhibition with stattic, highlighting a new immunotherapy approach to preventing melanoma metastasis.