A study in mice shows that the peptide LL‑37 (called CRAMP in mice) can push a type of immune cell, Th17, to become more suppressive and even die, through a p38 signaling route. This suggests that LL‑37 might actually dampen certain immune functions rather than boost them, especially in a tumor setting.

The effector function of tumor-infiltrated CD4⁺ T cells is readily suppressed by many types of immune regulators in the tumor microenvironment, which is one of the major mechanisms of immune tolerance against cancer. Cathelicidin-related antimicrobial peptide (CRAMP), the mouse analog of LL-37 peptide in humans, is a cationic antimicrobial peptide belonging to the cathelicidin family; however, its secretion by cancer cells and role in the tumor microenvironment (TME) remain unclear. In this study, we explored the possibility of an interaction between effector CD4⁺ T cells and CRAMP using in vitro-generated mouse Th17 cells. We found that CRAMP stimulates Th17 cells to express the ectonucleotidase CD73, while simultaneously inducing cell death. This finding suggested that CD73-expressing Th17 cells may function as immune suppressor cells instead of effector cells. In addition, treatment of pharmacological inhibitors of the transforming growth factor-beta (TGF-β) signaling pathway showed that induction of CD73 expression is mediated by the p38 signaling pathway. Overall, our findings suggest that tumor-derived LL-37 likely functions as an immune suppressor that induces immune tolerance against tumors through shaping effector Th17 cells into suppressor Th17 cells, suggesting a new intervention target to improve cancer immunotherapy.