FIG4 downregulation-arrested autophagy-lysosomal degradation of IL-18 drives lipid-associated macrophage polarization and immunotherapy resistance in triple-negative breast cancer.

Factor-induced gene 4 (FIG4) has been recently identified as a lipid-modifying enzyme that plays an important role in controls autophagolysosomal activity. However, the regulatory mechanisms and biological functions of FIG4 in cancer therapeutic resistance are not well defined. In this study, we identify that FIG4 as a regulator of IL-18 autophagy-lysosomal degradation, participating in the immunotherapy response in triple-negative breast cancer (TNBC). FIG4 overexpression markedly facilitate the autophagy-lysosomal degradation of IL-18 in the LAMP2A-dependent manner. Ubiquitinated IL-18 induced by FIG4 overexpression reduces its secretion, inhibiting the tumor infiltration of immune-suppressive lipid-associated macrophages (LAMs) and re-sensitizing TNBC to immune-checkpoint blockade. Notably, the combination of FIG4 overexpression or IL-18 neutralizing antibody (aIL-18) with PD-1 inhibitor (aPD-1) produces synergistic effects, effectively addressing certain limitations of current immunotherapeutic approaches in TNBC. In conclusion, these findings underscore a novel mechanism underlying the roles of FIG4-IL-18 axis in immunotherapy resistance. Targeting FIG4-IL-18 axis offers a tractable strategy to dismantle LAM-mediated immunotherapy resistance in TNBC.