Immunological biomarkers for precision stereotactic body radiation therapy in early-stage non-small cell lung cancer: a systematic review.

Abstract

Stereotactic body radiation therapy (SBRT) is a non-invasive alternative to surgery for the management of early-stage non-small cell lung cancer (ES-NSCLC). Despite excellent control rates, outcomes of SBRT are still heterogenous, and there is a clear need for biomarkers to guide treatment selection, estimate recurrence risk, or identify patients who may benefit from treatment intensification. Given the increasing role of immunotherapy in this setting, we conducted a systematic review to summarise the available evidence on prognostic and predictive immunological biomarkers in stage I-II NSCLC treated with curative SBRT. PubMed/MEDLINE, Scopus, Embase, and ClinicalTrials.gov were screened on 30th November 2025. Full-texts from database inception written in English were considered eligible if presenting the association between immunological biomarkers and oncological outcomes in patients treated with SBRT. Due to the heterogeneity of the included studies in terms of biomarkers, outcome definitions, and analytical approaches, neither a formal meta-analysis nor a GRADE assessment was performed. Consequently, statistical heterogeneity and publication bias were not formally assessed. Risk of bias was assessed with the Newcastle-Ottawa Scale (NOS). Ten studies, for a total of 1019 patients, met the inclusion criteria. Eight were retrospective cohorts, one was a prospective observational study, and one was a phase I trial. Overall, the included studies showed moderate-to-high methodological quality, with most achieving adequate follow-up and higher NOS scores, demonstrating adequate selection criteria, outcome ascertainment, and control of confounders. Median sample size was 82 (interquartile range 61-117). The most frequently investigated biomarkers were neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), with elevated baseline levels consistently associated with poorer survival. CD44 emerged as a potential predictive biomarker, with higher expression correlating with increased risk of recurrence after SBRT and validated in an external surgical cohort. Immune-profiling studies identified prognostic signatures-such as PD-1⁺, CD4 T cells and Th17 subsets-but none demonstrated predictive value for SBRT response. Current evidence highlights the predominance of prognostic, rather than predictive, biomarkers in ES-NSCLC treated with SBRT. While CD44 and other tumour microenvironment-related markers are promising, available data remain exploratory. Larger biomarker-driven studies are needed to enable personalised treatment allocation between surgery and SBRT and to guide rational use of systemic therapies in early-stage disease. The present work was conducted within the framework of the MONDRIAN trial.