Prognostic significance of immune phenotypes in patients with metastatic non-small cell lung cancer

Background. Non-small cell lung cancer is one of the leading causes of cancer-related mortality worldwide. Despite the introduction of immunotherapy, clinical responses remain heterogeneous. This necessitates the identification of reliable prognostic biomarkers to stratify patients according to their potential responsiveness to therapy. Purpose – to analyze the morphofunctional characteristics of the tumor immune microenvironment, to identify classes of immune phenotypes, and to evaluate their impact on survival in patients with metastatic non-small cell lung cancer. Materials and Methods. This retrospective cohort study included 86 patients treated with immune checkpoint inhibitors under routine clinical conditions. Immunohistochemical analysis of archival tumor tissue was used to assess the expression of CD8⁺ T lymphocytes, STAT6⁺, and the ratio of macrophage markers CD163⁺/CD68⁺. Data were processed using principal component analysis and hierarchical clustering. Group comparisons were performed using the Kruskal–Wallis test. Survival curves were constructed using the Kaplan–Meier method, with differences assessed via the log-rank test. Statistical significance was set at p < 0.05. Results. Three immune phenotypes were identified: immune-active (high CD8⁺ infiltration, low STAT6⁺ expression, and low CD163⁺/CD68⁺ ratio), immunosuppressive (low CD8⁺, high STAT6⁺, and high CD163⁺/CD68⁺), and neutral/mixed with intermediate values. The immune-active phenotype was associated with the most favorable progression-free survival (median >16.0 months) and overall survival (median >35.0 months), while the immunosuppressive phenotype demonstrated the poorest outcomes (5.1 and 8.8 months, respectively). Statistically significant differences in survival between phenotypes were confirmed by the log-rank test (p < 0.001). In multivariable Cox regression analysis, the CD163⁺/CD68⁺ ratio emerged as the only independent prognostic factor for both progression-free and overall survival (HR = 2.81 and 4.34, respectively; p < 0.001), highlighting the critical role of macrophage polarization in mediating the response to immunotherapy. Conclusions. The tumor immune microenvironment in metastatic non-small cell lung cancer can be classified into immune-active, neutral/mixed, and immunosuppressive phenotypes, with distinct effects on survival under immunotherapy. The CD163⁺/CD68⁺ ratio was identified as the key independent predictor of survival.