IL-33/ST2 signalling promotes tumor growth by regulating polarization of alternatively activated macrophages

Objective: Suppression of tumorigenicity 2 (ST2), the receptor for interleukin (IL)-33, has a critical role in tumor growth, angiogenesis, metastasis, and immune modulation. The IL-33/ST2 pathway is known to influence the polarization and function of macrophages, which is integral to modulating the tumor microenvironment. However, the precise role of IL-33/ST2 in tumors, particularly non-small cell lung cancer (NSCLC), has not been established. Methods: ST2 expression in NSCLC was analysed using a murine model and patient specimens. The effect of the IL-33/ST2 axis on macrophage polarization in NSCLC was determined. Results: Elevated ST2 expression was correlated with aggressive tumor growth. Specifically, ST2 expression on macrophages was associated with lung cancer progression and the absence of ST2 on macrophages was associated with diminished tumor growth. IL-33 promoted polarization of alternatively activated macrophages in an ST2-dependent manner that was mediated via the PI3K/ Akt signalling pathway. Moreover, IL-33 inhibited T-cell function by inducing the secretion of transforming growth factor beta from alternatively activated macrophages. Conclusions: Macrophages expressing ST2 can serve as promising therapeutic targets for NSCLC immunotherapy, highlighting the IL-33/ST2 axis as a potential target for future antitumor strategies.