We have revealed for the first time that polymetastatic (POL) melanoma cells can utilize both the secretory protein pathway (S100A11–Sec23a) and the exosomal crosstalk (miR‐487a‐5p) to transfer their ‘polymetastatic competency’ to the oligometastatic (OL) melanoma cells, via synergistic co‐targeting of the tumor‐suppressor Nudt21. Here, S100A11 is linked to melanoma.