The heterogeneity of tumor cells enables cancers to dynamically adapt to microenvironmental stresses during progression. However, the mechanism underlying the transformation and intercellular communication between heterogeneous tumor cells has remained elusive. Here, we report a “contagion model” that mediates intercellular transformation between heterogeneous tumor cells which facilitates tumor progression. Initially identifying heterogeneous expression of CXCR1, a receptor for interleukin-8, in head and neck squamous cell carcinoma (HNSCC) tumor cells, we found that CXCR1-High cells transformed CXCR1-Low cells into CXCR1-High cells through the secretion of small extracellular vesicles.We demonstrate that sEVs derived from interleukin-8-activated CXCR1-High cells contain high levels of ATP citrate lyase (ACLY) mediated this process.