Cancer Immunol Res. 2026 Jan 15. doi: 10.1158/2326-6066.CIR-24-1159. Online ahead of print.

ABSTRACT

Tumor-associated macrophages (TAMs) represent the main immune population infiltrating cancers, and their abundance is generally correlated with a poor prognosis. The acquisition of protumor properties by TAMs involves several mechanisms, including expression of immunosuppressive enzymes. In this study, we explored the role of the enzyme IL-4 induced gene 1 (IL4I1) expressed by TAMs in murine models of melanoma. We found that IL4I1 expression was increased in subsets of TAMs during spontaneous melanoma progression and this increase could be blocked by TNF-α, IL-12, and IL-1β co-neutralization. Macrophage-specific IL4I1 deletion delayed tumor onset and metastatic dissemination. Mechanistically, targeting IL4I1 restored antitumor functions of TAMs with increased antigen-presenting capacity and restored the proliferative and cytotoxic capacities of CD8+ T cells. Chemical blockade of IL4I1 partially reproduced these results. Overall, we demonstrate the key role of IL4I1 in TAM-mediated immune escape of melanoma. As most human tumors contain TAMs expressing IL4I1, our results may have implications for cancer immunotherapy.

PMID:41537775 | DOI:10.1158/2326-6066.CIR-24-1159