The study shows that the natural immune peptide LL‑37, when produced by certain immune cells, can actually help lung cancer grow by turning on a cell‑growth pathway (Wnt/β‑catenin). Higher levels of LL‑37 were found in lung tumors and linked to worse outcomes, meaning more of this peptide may be harmful rather than helpful.

<b>Rationale</b>: Antimicrobial peptides, such as cathelicidin LL-37/hCAP-18, are important effectors of the innate immune system with direct antibacterial activity. In addition, LL-37 is involved in the regulation of tumor cell growth. However, the molecular mechanisms underlying the functions of LL-37 in promoting lung cancer are not fully understood. <b>Methods</b>: The expression of LL-37 in the tissues and sera of patients with non-small cell lung cancer was determined through immunohistological, immunofluorescence analysis, and enzyme-linked immunosorbent assay. The animal model of wild-type and Cramp knockout mice was employed to evaluate the tumorigenic effect of LL-37 in non-small cell lung cancer. The mechanism of LL-37 involving in the promotion of lung tumor growth was evaluated <i>via</i> microarray analyses, recombinant protein treatment approaches <i>in vitro</i>, tumor immunohistochemical assays, and intervention studies <i>in vivo</i>. <b>Results</b>: LL-37 produced by myeloid cells was frequently upregulated in primary human lung cancer tissues. Moreover, its expression level correlated with poor clinical outcome. LL-37 activated Wnt/&#x3b2;-catenin signaling by inducing the phosphorylation of protein kinase B and subsequent phosphorylation of glycogen synthase kinase 3&#x3b2; mediated by the toll-like receptor-4 expressed in lung tumor cells. LL-37 treatment of tumor cells also decreased the levels of Axin2. In contrast, it elevated those of an RNA-binding protein (tristetraprolin), which may be involved in the mechanism through which LL-37 induces activation of Wnt/&#x3b2;-catenin. <b>Conclusion</b>: LL-37 may be a critical molecular link between tumor-supportive immune cells and tumors, facilitating the progression of lung cancer.