Recent advances and future perspectives in non-small cell lung cancer immunotherapy

Abstract

The introduction of immune checkpoint inhibitors has transformed therapeutic strategies for non-small cell lung cancer; however, the generalisation of data regarding their molecular mechanisms of action and predictors of therapeutic efficacy remains an important challenge. The aim of this study was to conduct a comprehensive analysis of the molecular and biological principles underlying immune checkpoint inhibitors, to identify prognostic biomarkers of treatment response, and to synthesise current combination immunotherapeutic strategies for non-small cell lung cancer. This work was performed as a systematic review of scientific publications in the PubMed, Web of Science, and Scopus databases for the period 2016-2025, using comparative analysis, systematic synthesis, and critical appraisal of randomised phase III trials, prospective multicentre cohort studies, and meta-analyses. In patients with PD-L1 expression ≥50%, pembrolizumab monotherapy was associated with a median overall survival of 26.3 months compared with 13.4 months for chemotherapy, with five-year survival rates of 31.9% and 16.3%, respectively. In contrast, the combination of immunotherapy and chemotherapy achieved approximately 20% five-year survival irrespective of PD-L1 expression. A high tumour mutational burden correlated with an objective response rate of 47.6%, compared with 27.3% in patients with low mutational burden, while high-grade microsatellite instability was associated with a 65% reduction in mortality risk (hazard ratio 0.35). It was established that KRAS/STK11 and KRAS/KEAP1 alterations are associated with an immunosuppressive phenotype and reduced efficacy of monotherapy, whereas the combination of anti-angiogenic agents with immune checkpoint inhibitors and chemotherapy achieved the longest median overall survival of 28.88 months. The findings provide a basis for the individualisation of therapeutic approaches using comprehensive biomarker panels and support the feasibility of multi-level patient stratification based on molecular genetic profiling, characterisation of the tumour microenvironment, and microbiome analysis to improve outcomes of immunotherapy in non-small cell lung cancer