Interleukin-6 at the Host-Tumor Interface: STAT3 in Biomolecular Condensates in Cancer Cells

It was recognized over 30 years ago that the polyfunctional cytokine interleukin-6 (IL-6) was an almost invariant presence at the host-tumor interface. The IL-6 in the tumor microenvironment was produced either by the cancer cell or by host stromal cells, or by tumor-infiltrating immune cells, or all of them. IL-6 effects in this context included local changes in tumor cell-cell and cell-substrate adhesion, enhanced motility, epithelial to mesenchymal transformation (EMT), and changes in cell proliferation rates in both solid tumors as well as hematologic dyscrasias. Locally produced IL-6 enhanced cancer-targeting functions of tumor-infiltrating macrophages and immune cells. Additionally, the sex-biased phenotype of certain cancers [e.g., hepatocellular carcinoma (HCC) which is 3-5-fold more common in men] was related to the inhibition of macrophage-derived IL-6 production by estradiol-17 beta (E2). In many circumstances, locally produced IL-6 reached the peripheral circulation and elicited systemic effects such as cachexia and paraneoplastic syndrome (including fever, increased erythrocyte sedimentation rate, increased levels of C-reactive protein in serum, hypoalbuminemia). This review highlights the EMT produced by IL-6 in cancer cells, as well as mechanisms underlying sex bias in HCC, enhanced IL-6 expression in cancer cells resulting from mutations in p53, consequent alterations in STAT3 transcriptional signaling, and the newer understanding of STAT3 nuclear bodies in the cancer cell as phase-separated biomolecular condensates and membraneless organelles (MLOs). Moreover, the perplexing issue of discrepant measurements of IL-6 in human circulation using different assays, especially in patients undergoing immunotherapy, is discussed. Additionally, the paradoxical chaperone (enhancing) effect of anti-IL-6 "neutralizing" antibodies on IL-6 in vivo and consequent limitations of immunotherapy using anti-IL-6 mAb is considered.