IL-6 trans-signaling in cancer metabolism, multidrug resistance, and chronic inflammation

Interleukin-6 (IL-6) trans-signaling plays a pivotal role in cancer progression and the regulation of metabolic pathways, exhibiting significant tissue specificity. IL-6, a pleiotropic cytokine, mediates cellular communication and inflammatory responses through distinct pathways with both beneficial and detrimental effects. Trans-signaling occurs when IL-6 binds to its soluble receptor (sIL-6Rɑ), forming a complex with the signal transducer gp130. This pathway is associated with a pro-inflammatory phenotype, and not by chance, IL-6 trans-signaling also contributes to tumorigenesis, promoting angiogenesis, resistance to apoptosis, and metastasis. This review highlights the significance and tissue-specificity of IL-6 trans-signaling activation in cancer biology, metabolism, and drug resistance, underscoring its potential as a therapeutic target. Indeed, IL-6 trans-signaling influences metabolic processes by altering glucose and lipid metabolism, thereby supporting energy demands from rapidly proliferating cancer cells. Through metabolic reprogramming IL-6 trans-signaling not only fuels cancer cell growth but also contributes to the development of a tumor-friendly microenvironment that is IL-6-dependent and self-sustaining. These events contribute also to development of multidrug resistance during cancer progression. An in-depth understanding of the molecular mechanisms underlying IL-6 trans-signaling will offer novel insights into precision medicine for cancer treatment and for the sensitization of cancer cells to antitumor weapons.