The therapeutic exploitation of IL-1 in cancer: Controlling tumor progression and resistance to targeted therapies

: The interleukin-1 (IL-1) superfamily encompasses a group of cytokines with central roles in inflammation and immune regulation. IL-1 is directly implicated in activating survival and proliferative pathways in transformed cells, orchestrating the angiogenic switch, remodeling the extracellular matrix, and driving invasion and metastatic colonization. Here we review the diverse cellular sources of IL-1, spanning from monocytes to non-immune cell types such as cancer cells, stromal fibroblasts, and endothelial cells. We also discuss IL-1-neutralizing strategies, including monoclonal antibodies, decoy receptors, and competitive receptor antagonists, currently or previously tested in clinical trials, with particular attention to the most recent and unsuccessful combinations, notably with immune checkpoint inhibitors. Finally, we highlight emerging evidence linking IL-1 axis to resistance against Epidermal Growth Factor Receptor (EGFR)-targeted therapies. Together, these findings suggest that targeting the IL-1 axis in combination with EGFR-TKIs could impair tumor initiation and relapse and mitigate inflammation-driven therapeutic escape, offering a promising avenue for future clinical development.