IL‑6: A key player in the EGFR‑TKI‑resistant tumor microenvironment and its therapeutic implications (Review)

IL-6, a pleiotropic inflammatory cytokine predominantly secreted by fibroblasts, myeloid-derived suppressor cells, tumor-associated macrophages and tumor cells, is associated with poor prognosis of and therapeutic resistance in non-small cell lung cancer (NSCLC).The activation of signaling pathways, including the JAK/STAT3, MAPK and PI3K/AKT pathways, promotes tumor survival.Furthermore, the IL-6/JAK/STAT3 signaling axis has emerged as a key driver of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) resistance, orchestrating intricate crosstalk within the tumor microenvironment (TME) to promote cell survival and immunosuppression.The present review synthesized current evidence on the dual role of IL-6 in mediating EGFR-TKI resistance and blunting anti-tumor immunity.The present review highlights the preclinical rationale for combining IL-6 blockade with EGFR-TKI or immune checkpoint inhibitors to overcome refractory disease.The present review also highlights the structure, molecular mechanisms and clinical insights of IL-6 in the TME of EGFR-mutant NSCLC and may provide optimized therapeutic strategies for EGFR-TKI-refractory NSCLC.