In recent years, the integration of immunotherapy with chemotherapy has transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC). This combination therapy leverages the immune system’s ability to target cancer cells while simultaneously utilizing cytotoxic agents to attack tumors. Despite its promise and widespread adoption as standard care, the pressing challenge remains: how to accurately predict which patients will benefit most from this therapeutic approach. A groundbreaking study published in BMC Cancer sheds light on this challenge by introducing a novel prognostic score based on the neutrophil-to-lymphocyte ratio (NLR), a readily accessible blood marker, that can effectively forecast patient outcomes in this clinical setting.
The research was conducted retrospectively on a cohort of 171 patients diagnosed with advanced NSCLC who underwent combined immune checkpoint inhibitor (ICI) therapy and chemotherapy. The investigators meticulously gathered clinical data alongside peripheral blood inflammatory markers to construct predictive models that could serve as reliable biomarkers for therapy efficacy and prognosis. Their focus centered on the systemic inflammatory response, particularly examining the NLR, fibrinogen levels, and other hematologic indices as potential indicators of therapeutic success or failure.
Among patients receiving first-line ICI plus chemotherapy, the study identified a critical threshold for pre-treatment NLR: values exceeding 3.3 correlated strongly with diminished progression-free survival (PFS). Elevated fibrinogen levels (greater than 3.196 g/L) similarly signaled poorer treatment outcomes. These findings underscore the interplay between systemic inflammation and cancer progression, highlighting how an imbalanced immune milieu marked by neutrophilia relative to lymphocytes may foster an environment conducive to tumor resistance and progression.
Crucially, the researchers developed a composite prognostic score combining NLR and fibrinogen—termed the NLR-Fib (NF) score—which demonstrated superior predictive accuracy compared to programmed cell death ligand 1 (PD-L1) expression assessed from tumor biopsies. PD-L1 has traditionally been utilized as a biomarker to select candidates for immunotherapy, but its variability and limitations have prompted the search for alternative or complementary measures. The NF score, derived from routine blood tests, offers a noninvasive, cost-effective, and reproducible tool for risk stratification in clinical practice.
The study also delved into a subset of NSCLC patients harboring targetable oncogenic driver mutations and treated with ICI plus chemotherapy beyond the first line. Here, a slightly higher NLR threshold of 3.53 was indicative of worse therapeutic responses and independently predicted both progression-free and overall survival (OS). Interestingly, prior duration of tyrosine kinase inhibitor (TKI) therapy exceeding 12 months emerged as an independent favorable prognostic factor for overall survival. This observation suggests that sustained disease control with targeted agents before immunotherapy may prime tumors for better responsiveness.
Further complexity was added by the identification of other factors influencing outcomes in this patient group. Secondary mutations such as the epidermal growth factor receptor (EGFR) T790M variant were associated with reduced PFS, as were a platelet-to-lymphocyte ratio (PLR) above 196.81 and hypoalbuminemia with albumin levels below 40.25 g/L. These markers collectively reflect the tumor’s evolving biology and systemic host factors that potentially modulate therapeutic efficacy.
Building on these insights, the authors formulated another prognostic metric termed the NLR-TKI-PFS (NTP) score, incorporating NLR levels and prior TKI progression-free survival time. This score stratified patients into three distinct risk categories — favorable, intermediate, and poor — correlating with median OS of 21, 12, and 5.3 months, respectively. Such a tool holds promise for guiding personalized treatment decisions and counseling patients regarding their prognosis in advanced disease stages.
The impact of this study extends beyond its immediate clinical findings. It challenges the current reliance on tissue-based biomarkers like PD-L1, which are often hampered by tumor heterogeneity, sampling bias, and dynamic expression changes. By contrast, systemic inflammation markers measured through blood tests provide a holistic snapshot of the host-tumor interaction and can be serially monitored to adapt treatment strategies.
Moreover, the accessibility and cost-effectiveness of blood-based biomarkers ensure the applicability of these prognostic scores even in resource-limited settings. As immunotherapy revolutionizes oncology care worldwide, such practical tools are imperative to optimize patient outcomes, avoid unnecessary toxicities, and contain healthcare costs.
The biological rationale underpinning the prognostic significance of NLR and fibrinogen is grounded in their roles in cancer pathophysiology. Neutrophils promote tumor progression by secreting pro-angiogenic factors and immunosuppressive cytokines, while lymphocytes, particularly cytotoxic T cells, are critical for anti-tumor immunity. A high NLR thus reflects a state of immune dysregulation favoring tumor escape. Elevated fibrinogen, a key coagulation factor, is implicated in tumor metastasis and inflammatory processes, further aggravating disease progression.
Beyond the statistical associations, this study advocates for integrating inflammatory markers into comprehensive clinical algorithms. Such integration may improve patient selection for immunotherapy and inform the timing of therapeutic interventions, combining or sequencing agents to overcome resistance mechanisms.
Future directions informed by this work include prospective validation trials to confirm the robustness of the NF and NTP scores across diverse populations and treatment regimens. Additionally, research into mechanistic links between inflammation and immunotherapy response could unveil novel therapeutic targets, potentially allowing modulation of the inflammatory milieu to enhance treatment efficacy.
Importantly, this research touches upon the personalized medicine paradigm, where nuanced patient stratification transcends conventional histological and genetic classifications. By incorporating systemic factors reflective of the host-tumor ecosystem, clinicians can better predict clinical trajectories and tailor interventions accordingly.
In summary, the study published in BMC Cancer heralds a promising advance in the prognostication of advanced NSCLC patients receiving ICI plus chemotherapy. Through innovative use of simple hematologic parameters, it provides a window into the complex interplay between cancer, host immunity, and treatment response. These insights bear the potential to refine therapeutic precision, improve survival outcomes, and ultimately transform patient care paradigms in oncology.
Subject of Research: Prognostic biomarkers in advanced non-small cell lung cancer treated with immunotherapy plus chemotherapy.
Article Title: Neutrophil-to-lymphocyte ratio-based prognostic score can predict outcomes in patients with advanced non-small cell lung cancer treated with immunotherapy plus chemotherapy.
Article References:
Liao, S., Sun, H., Lu, H. et al. Neutrophil-to-lymphocyte ratio-based prognostic score can predict outcomes in patients with advanced non-small cell lung cancer treated with immunotherapy plus chemotherapy.
BMC Cancer 25, 697 (2025). https://doi.org/10.1186/s12885-025-13811-y
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