IL-6 drives chemoimmunotherapy resistance in NSCLC by reprogramming myeloid cells and impairing cytotoxic lymphocyte function.

Primary resistance to first-line chemoimmunotherapy remains a significant challenge in treating advanced non-small cell lung cancer (NSCLC). Although cytokines such as interleukin-6 (IL-6) have been implicated in resistance to immune checkpoint inhibitor (ICI) monotherapy, their predictive value for chemoimmunotherapy outcomes and the underlying mechanisms are less defined. This study investigated the prognostic significance of the baseline plasma IL-6 levels and the role of this cytokine in shaping the tumour immune microenvironment (TIME) of NSCLC. Here, we retrospectively analysed data on 123 advanced NSCLC patients treated with anti-PD-1 inhibitors plus chemotherapy. Baseline plasma IL-6 levels were measured via ELISA. Progression-free survival (PFS) and overall survival (OS) were assessed via Kaplan-Meier and Cox regression analyses. We established murine lung adenocarcinoma (LLC) and squamous cell carcinoma (KLN205) models with IL-6 overexpression or inhibition and treated them with anti-PD-1 therapy ± chemotherapy. Tumour growth was monitored, and single-cell RNA sequencing (scRNA-seq) was performed on tumour-infiltrating immune cells. The results showed that patients with high baseline plasma IL-6 levels (>7.002 pg/mL) exhibited significantly worse PFS (median: 7.20 vs. 16.63 months, P = 0.001) and OS (median: 15.63 vs. 32.80 months, P = 0.001) than those with low baseline levels. A high IL-6 level was an independent predictor of worse PFS (HR = 2.42, P < 0.001) and OS (HR = 2.96, P < 0.001) and was correlated with progressive disease (PD, P = 0.018). In murine models, IL-6 overexpression diminished the antitumour efficacy of anti-PD-1 therapy combined with chemotherapy. Moreover, scRNA-seq analysis revealed that IL-6 overexpression skewed macrophage polarisation toward immunosuppressive phenotypes (characterised by Hilpda and Nr4a1 expression) and reduced the proportion of cytotoxic CD8+ T-cells while increasing the proportion of regulatory T-cells (Tregs). Conversely, IL-6 inhibition promoted an immunostimulatory macrophage phenotype (characterised by increased Ccl8 expression) and enhanced CD8+ T-cell infiltration and function. A high IL-6 level was also correlated with impairment of NK cell degranulation pathways. These findings uncovered that an elevated baseline plasma IL-6 level is a robust independent predictor of primary resistance and poor survival in advanced NSCLC patients receiving chemoimmunotherapy. Mechanistically, IL-6 drives formation of an immunosuppressive TIME by promoting protumour macrophage polarisation. This, in turn, suppress cytotoxic T cell infiltration, promoting Treg expansion, and impairing NK cell function, indicating that the targeting of IL-6 represents a promising strategy to overcome resistance to chemoimmunotherapy.