Cancer poses a significant global public health threat, with its disease burden on the rise. In 2022, there are expected to be around 20 million new cancer cases and 10 million deaths worldwide. Projections indicate that by 2050, the annual number of new cases will increase by 77%, reaching 35 million (1). Although targeted therapy and immunotherapy have revolutionized cancer treatment, increasing the overall five-year relative survival rate to 68% (2), survivors still face many complex challenges, including the risk of recurrence, uncertainty about death, and secondary complications caused by psychological barriers (3). In this context, constructing a precise prognostic prediction system has become the focus of clinical research. In previous studies, the mechanism by which inflammation is associated with cancer progression and risk of death has been widely confirmed (4, 5). The neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio(PLR) (6), the systemic immune-inflammation index(SII) (7), the albumin-to-globulin ratio (AGR), and the prognostic nutritional index (PNI) (8) have all been shown to correlate with tumor prognosis.

It is worth noting that nutritional status is involved in the cancer process through bidirectional regulation of pro-inflammatory/anti-inflammatory, suggesting a complex interaction between inflammation-nutrition-cancer (9). Based on this, researchers are systematically integrating inflammatory and nutritional indicators to construct a new assessment system: neutrophils, as a core component of innate immunity, play a dual role in the tumor microenvironment, both anti-tumor and pro-cancer (10, 11); albumin, as a classic nutritional marker, its dynamic changes have important predictive value for disease prognosis (12). The Bernard team innovatively proposed the neutrophil-albumin ratio (NPAR) concept, which has been shown to be significantly effective in predicting the response to neoadjuvant therapy in colorectal cancer (13). Subsequent studies have further verified the universality of NPAR for prognostic assessment of oral cancer (14), gastrointestinal tumors (15), breast cancer (16), lung cancer (17), pancreatic cancer (18), and bladder cancer. Among cancer patients, the occurrence of cachexia is common; this syndrome of malnutrition is associated with cancer, chronic kidney failure, and other chronic diseases (19). Additionally, the incidence of acute and chronic kidney failure in cancer patients is often associated with mortality (20). However, there is currently a lack of research on the correlation between nutrition, kidney function, and cancer.

To address this critical knowledge gap, this study systematically examined the predictive efficacy of NPAR for all-cause mortality and cause-specific mortality in cancer survivors, utilizing long-term follow-up data from the 2003–2018 cohort of the National Health and Nutrition Examination Survey (NHANES). Notably, this study innovatively introduces the analysis of mediation effects, revealing for the first time the mediating mechanism of renal function indicators between NPAR and mortality, thereby providing a multi-dimensional theoretical foundation for the clinical application of NPAR as a new prognostic biomarker.

This study utilized data from NHANES and revealed for the first time that NPAR is an independent predictor of all-cause and cancer-specific mortality risk in cancer survivors. The core findings showed that for every 1-unit increase in NPAR, the risk of all-cause mortality increased by 10%, the risk of cancer-related mortality increased by 6%, and the risk of non-cancer mortality increased by 12%. This dose-dependent association remained robust in multivariate adjusted models. RCS analysis further revealed a nonlinear relationship between NPAR and mortality risk, with a steep inflection point in the risk of all-cause mortality when NPAR exceeded 12.84. Finally, mediation analysis clarified that renal function impairment is a key pathway through which NPAR affects prognosis: 23.08% of the risk of all-cause mortality mediated by NPAR is driven by a decline in eGFR, and 21.97% of the risk of non-cancer mortality is attributed to worsening renal function.

Neutrophils represent a significant component of the innate immune system, with their hematopoietic stem cells generated through evolutionary processes. In the tumor microenvironment, neutrophils are classified as tumor-associated neutrophils (21). Numerous studies have demonstrated that neutrophils exhibit plasticity within the tumor host; they can be categorized into anti-tumor (N1) and pro-tumor (N2) phenotypes based on their roles in tumor dynamics. Neutrophils of the N1 phenotype may exert anti-tumor effects via reactive oxygen species (ROS)-associated pathways, while pro-tumor mechanisms of N2 phenotype neutrophils may involve neutrophil elastase (NE) and matrix metalloproteinases (22–24). Albumin can bind to pro-inflammatory cytokines, such as IL-6, and neutralize lipopolysaccharides (LPS), thereby preventing the conversion of neutrophils to the N2 phenotype. In vitro studies (25) have demonstrated that albumin can inhibit the formation of NETs (neutrophil extracellular traps) by N2 neutrophils, thereby reducing their protective effect on tumor cells. A decrease in albumin levels, which is commonly observed in high NPAR states, increases the availability of free IL-6, which in turn induces N2 polarization. This creates a vicious cycle: N2 neutrophils secrete more IL-6, further inhibiting hepatic albumin synthesis, leading to even higher NPAR levels and ultimately resulting in poorer prognosis (25). The N1/N2 ratio has also been suggested as a prognostic factor in hepatocellular carcinoma, where a higher N1/N2 ratio in the tumor microenvironment correlates positively with prognosis. Conversely, a high N1/N2 ratio in peritumoral tissues has been associated with poorer prognostic outcomes (26). Additionally, tumor-associated neutrophils may be influenced by metabolic processes, leading to increased expression of hypoxia-inducible factor 1α (HIF-1α), which promotes angiogenesis, glycolysis, and gene upregulation, ultimately advancing tumor progression (27–30). Furthermore, past studies have demonstrated that neutrophil infiltration is regulated by chemokine pathways such as CXCL/CXCR2, which are associated with either improved or worsened outcomes in different cancer types, highlighting their complex roles in cancer progression (31, 32).

Neutrophils and lymphocytes serve as critical and easily accessible markers of inflammation; the significance of the neutrophil-to-lymphocyte ratio in prognosing various diseases has garnered considerable interest. Elevations in this ratio may constitute an important risk factor for increased cardiovascular mortality among cancer survivors (33). Importantly, inflammation among cancer survivors is routinely correlated with nutritional status, and recent studies indicate that cancer patients exhibit a heightened risk of malnutrition, with their nutritional and immune statuses serving as significant predictors of tumor development and outcomes (12, 33, 34). In the context of disease prediction, albumin levels are closely correlated with inflammation and can serve as a marker for clinical stability when assessing nutritional status (35, 36). Albumin and globulin represent the primary components of serum proteins, with numerous studies confirming their efficacy as indicators of nutritional and inflammatory status in cancer progression. Their prognostic significance has been established across multiple cancers, including non-small cell lung cancer, gastric cancer, colorectal cancer, and breast cancer (37–40).

Several comprehensive indicators have been used to assess inflammation and nutritional status in cancer patients, including hemoglobin, albumin, lymphocytes, and platelets (HALP score) (41), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) (6), prognostic nutritional index (PNI) (8), and the systemic immune-inflammation index (SII) (7). Compared to these indices, NPAR has distinct advantages as it combines a direct measure of innate immune activity (neutrophil percentage) with reliable indicators of nutritional and inflammatory status (albumin). While NLR and PLR reflect immune imbalance, and PNI and HALP include nutritional components, NPAR provides a more comprehensive assessment of systemic inflammation and catabolic status, which may explain its robust predictive performance in our cohort.

The NPAR integrates inflammatory and nutritional factors to provide a comprehensive assessment of an individual’s inflammatory and nutritional status, and it was first introduced in 2016 by Bernard et al., demonstrating its potential predictive value in cancer (13). Numerous studies have supported the predictive validity of NPAR in various chronic diseases, revealing a positive correlation between high NPAR and both all-cause mortality and cardiovascular mortality in patients with hypertension and diabetes (42, 43). Additionally, elevated NPAR has been implicated as a risk factor for stroke (44). In the realm of tumor-specific survival, a growing body of research has established NPAR’s predictive value in patients with bladder cancer undergoing surgery after neoadjuvant chemotherapy, linking higher NPAR to lower overall tumor survival. Conversely, in oral squamous cell carcinoma, high NPAR has been associated with poorer overall survival and disease-free survival in patients (14, 45). A multicenter cohort study has shown high NPAR to be independently associated with all-cause mortality in individuals with cancer (46), aligning with our findings that indicate that higher NPAR correlates with poorer prognoses among cancer survivors. In terms of all-cause mortality, these results suggest that higher NPAR may be associated with an increased mortality risk, and we have identified possible inflection points. Furthermore, our additional analyses concerning cancer-specific and non-cancer mortality led to similar conclusions, indicating that elevated NPAR is associated with an increased risk of both cancer-specific and non-cancer-related deaths.

A novel finding of this study is the mediating role of renal function in the association between NPAR and mortality. Renal impairment may exacerbate systemic inflammation and malnutrition through several mechanisms. The interaction mechanism between renal dysfunction and systemic inflammation, as well as malnutrition, suggests that renal impairment (evidenced by decreased estimated glomerular filtration rate) is not an isolated pathological state but forms a “vicious cycle” through various pathways involving systemic inflammation and malnutrition, thereby exacerbating the mortality risk among cancer survivors. From an inflammatory amplification perspective, the kidneys typically maintain inflammatory homeostasis by clearing circulating inflammatory mediators (such as tumor necrosis factor-alpha and interleukin-6), metabolizing reactive oxygen species (ROS), and inhibiting the overactivation of neutrophils. When estimated GFR (eGFR) declines, this “inflammatory clearance capacity” is severely impaired: accumulated inflammatory factors (such as interleukin-6) further activate neutrophils and promote the formation of neutrophil extracellular traps (NETs), a process associated with elevated NPAR in this study. Activated NETs exacerbate Toll-like receptor 4/NF-κB signaling in renal tubules, triggering a more intense local renal inflammatory response and establishing a positive feedback loop of “renal inflammation → systemic inflammation → renal injury” (47, 48).Second, hypoalbuminemia creates a vicious cycle by inhibiting vascular endothelial growth factor (VEGF) signaling and mTORC1-mediated autophagy repair mechanisms, a process that has been validated in mouse models (49, 50). Notably, the S100A8/A9 proteins secreted by neutrophils establish positive feedback with hypoalbuminemia through bidirectional regulation — the former inhibits HNF-4α, a key factor in liver albumin synthesis, while the latter promotes the further release of NETs by upregulating HMGB1 (51). Importantly, the downregulation of Klotho expression in renal tubules not only aggravates phosphate retention and vascular calcification but also maintains the stemness of tumor cells through the Wnt/β-catenin pathway (52), suggesting that the imbalance of the Klotho/FGF23 axis may be a central mediator in the “renal-cancer dialogue.” Future studies should combine single-cell sequencing to elucidate cell interactions in the renal microenvironment and develop targeted intervention strategies aimed at clearing NETs or regulating the albumin-VEGF axis.

However, the underlying mechanisms through which NPAR contributes to increased mortality remain incompletely understood. Current studies have predominantly focused on inflammatory mechanisms, nutritional status, and immune dysregulation in the context of tumorigenesis, while the role of renal function has been relatively underexplored. Importantly, our mediation analysis identifies renal impairment (reflected by reduced eGFR) as a critical intermediary pathway linking NPAR to poor outcomes. Neutrophils may exert pro-tumorigenic effects through the secretion of cytokines and chemokines, the formation of neutrophil extracellular traps (NETs), and intercellular interactions, thereby promoting tumor angiogenesis, cancer cell proliferation, and metastasis (11). Notably, impaired renal clearance capacity due to decreased eGFR exacerbates systemic inflammation by failing to effectively remove pro-inflammatory cytokines (e.g., IL-6, TNF-α), which in turn further activates neutrophils and promotes NET formation. Meanwhile, albumin—a key component of NPAR—is not only a marker of nutritional status but also possesses anti-inflammatory properties. It has been demonstrated that serum albumin can inhibit NET formation in vitro by neutralizing activators such as lipopolysaccharide (LPS) (25). In the setting of renal dysfunction, hypoalbuminemia may intensify this vicious cycle by impairing antioxidant and endotoxin-neutralizing capacities, thereby amplifying neutrophil-mediated inflammation and organ damage. Therefore, renal dysfunction serves as both a contributor to and a consequence of imbalanced inflammatory-nutritional status, forming a self-reinforcing cycle that ultimately increases mortality risk. Nevertheless, the precise mechanisms underlying NPAR’s predictive value, particularly its interplay with renal pathways, warrant further investigation in future studies.

It is important to acknowledge the potential heterogeneity across different cancer types in our study. The biological behavior, tumor microenvironment, and treatment modalities vary substantially among malignancies (e.g., solid tumors vs. hematologic cancers, or hormone-driven vs. inflammation-driven cancers). These differences could undoubtedly influence the relationship between systemic inflammation/nutrition and patient survival. This study, by design, focused on the general population of cancer survivors to provide an overarching insight into the NPAR-mortality link. This approach has the advantage of identifying a biomarker with broad applicability but may obscure its cancer-specific performance. Future research is imperative to validate and calibrate the prognostic value of NPAR within homogenous cohorts of specific cancer types to guide precise clinical application.

This study does have some limitations. First, it is a retrospective study, and its design does not completely eliminate the possibility of selection bias. Although various confounding factors have been adjusted for, residual confounding (such as unmeasured lifestyle factors and genetic background) might still affect the results. Second, due to the observational design, the possibility of reverse causation cannot be fully excluded (for instance, elevated NPAR before death may reflect end-stage pathological states). Third, conclusions drawn from the NHANES U.S. population may not be directly applicable to other ethnic groups or healthcare systems, requiring further validation for external applicability. Finally, although the NHANES is nationally representative and features a rigorous research design, it lacks internal validation from independent clinical cohorts. Future studies should validate our findings in prospective, multi-center cohorts to enhance clinical translatability.

This study identifies the NPAR as a novel prognostic biomarker for mortality in cancer survivors. Elevated NPAR independently correlates with increased risks of all-cause, cancer-specific, and non-cancer mortality. Mediation analysis identifies renal dysfunction as a key pathway connecting NPAR to adverse outcomes, highlighting the interplay between systemic inflammation, nutrition, and kidney health. These findings support NPAR’s clinical utility for risk stratification and advocate for interventions targeting the inflammation-nutrition-kidney nexus to improve survival.