Djebri Nihel Chahinez, Zoudji Souad, Messaoud Aida, Messali Rabia, Loudjedi Salim, Aribi Mourad
Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria.
Laboratory of Applied Molecular Biology and Immunology, W0414100, University of Tlemcen, 13000 Tlemcen, Algeria; Surgery Department B of Tlemcen University Hospital Center, 13000 Tlemcen, Algeria.
Int Immunopharmacol. 2025 Oct 30;164:115299. doi: 10.1016/j.intimp.2025.115299. Epub 2025 Aug 9.
Colorectal cancer (CRC) generates a complex tumor microenvironment (TME) known to profoundly alter the function and phenotype of immune cells, including monocytes. Key aspects of this environment can be mimicked by tumor-conditioned medium (TCM). Metformin has emerged as a promising candidate to counteract TCM-induced immune and inflammatory dysregulation. Therefore, this study aimed to evaluate the effects of metformin on NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome expression, monocyte subset distribution, and lipid droplet (LD) accumulation upon exposure to colorectal TCM.
Assays were performed on primary human monocytes exposed to colorectal TCM in the presence or absence of metformin.
TCM significantly increased nitric oxide (NO, p < 0.001) and hydrogen peroxide (HO, p < 0.001) production, intracellular free calcium ions (Ca) (p < 0.001) levels, expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB p65/RelA, p < 0.001), NLRP3 (p < 0.01), and interleukin-1 beta (IL-1β, p < 0.0001), as well as intracellular triacylglycerols (TAGs, p < 0.05), total cellular cholesterol content (CHOL, p < 0.001), and lipid droplet accumulation (p < 0.05). It also impaired phagocytic activity (p < 0.05) and altered monocyte phenotype, along with a shift toward a CD14, CD16 phenotype (p < 0.0001 for both markers). Notably, metformin treatment exerted broad and significant reversing effects, specifically on respiratory burst (NO, p < 0.05; HO, p < 0.01), Ca levels (p < 0.01), NF-κB p65/RelA and NLRP3 expression, and IL-1β production (p < 0.0001 for all), and the lipid droplet accumulation (p < 0.0001), TAGs (p < 0.001), and CHOL (p < 0.01). Metformin also significantly restored CD14 expression (p < 0.05) and increased CD14 monocyte frequency (p < 0.01), while reducing CD16 expression (p < 0.05) and CD16 monocyte frequency (p < 0.01). However, it had no significant effect on phagocytosis in TCM-exposed monocytes (p > 0.05).
Our findings highlight metformin's selective immunometabolic reprogramming capacity in monocytes exposed to colorectal tumor-derived signals, supporting its potential as a context-specific immunomodulator. This study lays the groundwork for future translational research on metformin as an adjunctive agent in inflammation-driven tumor settings.
