Understanding the intracellular role of IL1α in regulation of immune suppressive myeloid cells in breast cancer 2260588

Abstract

Breast cancer remains one of the most prevalent and deadly malignancies worldwide. The tumor microenvironment (TME) critically shapes tumor progression and immune regulation through cytokine signaling. Among these, interleukin-1 alpha (IL1α) is a key mediator of breast cancer—associated immunosuppression. We initially identified IL1α produced by CX3CR1+ macrophage subset within the TME. Deletion of IL1α reduced tumor growth and depleted this population, suggesting IL1α-driven myeloid reprogramming. We hypothesize that IL1α deficiency reprograms myeloid differentiation from monocyte-derived suppressive macrophages to inflammatory macrophage. An in vitro bone marrow—derived macrophage (BMDM) model from wild-type (WT) and IL1α knockout (KO) mice was used to assess IL1α-dependent differentiation. Flow cytometry and qPCR characterized CD11b+CD11c+MHCII+ subsets and quantified inflammatory (iNOS, CD80) versus inhibitory (Arginase-1, CD206) markers. Functional assays, including T-cell proliferation and MDSC activity, evaluated immunoregulatory capacity. Seahorse analysis and mass spectrometry assessed mitochondrial metabolism and electron transport chain (ETC) integrity. IL1α KO BMDMs showed reduced F4/80 and CX3CR1 expression, a shift from CD11b+CD11c+MHCII^low to MHCII^high cells upon LPS activation, decreased inhibitory markers, and elevated inflammatory mediators. These macrophages exhibited reduced T-cell suppression and MDSC activity. Neutralization of extracellular IL1α in WT cells did not reproduce KO effects, supporting an intracellular role. IL1α loss impaired oxidative phosphorylation, and peptide inhibitor blocking IL1α mitochondrial localization reproduced this phenotype. Our results show IL1α as a regulator of mitochondrial metabolism and myeloid differentiation. By stabilizing the ETC, IL1α sustains immunosuppressive macrophages, whereas its loss promotes inflammatory, anti-tumor myelopoiesis, identifying IL1α as a potential therapeutic target in breast cancer. n/a Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)