 Collections of immune cells called ectopic lymphoid-like structures, or ELSs, have long been known to counteract the development of malignant tumors. They often form at sites of chronic inflammation, which without ELSs could otherwise trigger cancer initiation. But a recent study has shown that ELSs are a key factor in promoting the development of hepatocellular carcinoma, the most common type of liver cancer and the second leading cause of cancer-related death worldwide. A better understanding how ELSs foster malignant tumor growth could help to identify new targets for liver cancer prevention or therapy. This recently published study examined ELS formation in both human patients with hepatocellular carcinoma, or HTC, and mice to determine the role of these immune cell clusters in HTC initiation. In the patients, a high prevalence of ELSs in the liver increased the risk of developing new tumors and decreased survival after tumors are surgically removed, indicating that ELSs play a detrimental role in this type of liver cancer. ELS formation in the patient's liver was also associated with increased activity of specific proteins involved in inflammation. To further characterize how ELSs form and contribute to HTC initiation, the authors studied mice with high activity of these proteins in the liver. The mice, which exhibited liver ELSs comparable to those seen in human HTC patients, spontaneously developed HTC. The earliest malignant liver cells first appeared within these clusters and multiplied over time, ultimately moving out of the ELSs to establish visible, aggressive tumors. The presence of these early cancer cells in ELSs was confirmed and biopsied human liver tissue as well. Moreover, depleting the ELSs in the mice hindered the initiation of HTC. In a final set of experiments, it was found that the immune cells in each ELS provide stimulatory chemical signals to the early cancer cells and that these cancer cells may later become self-sufficient by generating their own stimulatory chemical signals. This study thus indicates that ELSs are a key factor that promotes HTC development, resulting in a poor prognosis. This is in sharp contrast to the role of this immune cell cluster in several other cancers, revealing a dark side of the immune response in liver cancer. Further studies should assess the possible negative effects of ELSs induced by cancer therapies that stimulate the immune response. Still, ELSs may prove to be an effective target for treating or even preventing HTC, such as by blocking the chemical signaling that triggers early cancer cell migration and malignant tumor growth.