Introduction
Triple-negative breast cancer (TNBC) represents an aggressive molecular subtype of breast cancer, accounting for 15–20% of all cases (1,2). Despite advances in comprehensive treatment strategies, TNBC remains characterized by early relapse and a high propensity for distant metastasis (3–5). Owing to the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2, patients receive limited benefits from endocrine or targeted therapies and have been shown to experience markedly worse overall survival (OS) compared with other breast cancer molecular subtypes, particularly hormone receptor-positive and HER2-positive disease (6–8). Although initially chemosensitive, TNBC frequently develops drug resistance, contributing to early relapse, distant metastasis and reduced disease-free survival and OS (9). Current prognostic systems based on tumor size, lymph node status and histologic grade insufficiently capture the biological heterogeneity of TNBC or the important influence of host-related factors (10,11). Growing evidence has indicated that systemic host responses, particularly immune and nutritional status, serve central roles in tumor progression and treatment response (12,13). Thus, biomarkers integrating host immunity and nutrition may offer more accurate prognostic insight within TNBC management.
Systemic inflammation and nutritional deficiency are key determinants of cancer initiation, progression and survival (14). Chronic inflammation promotes immune evasion, angiogenesis and epithelial-mesenchymal transition through cytokine-mediated pathways including IL-6/STAT3, TNF-α/NF-κB and TGF-β (15–17). Concurrently, malnutrition impairs immune competence, leading to compromised T-cell activation, macrophage dysfunction and weakened antitumor responses (18,19). Composite indices reflecting inflammation or nutrition, such as the modified Glasgow prognostic score (mGPS), prognostic nutritional index (PNI), systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), have shown prognostic utility in a number of malignancies, including TNBC (20–23). Elevated NLR independently predicted shorter disease-free survival in early-stage TNBC (24), while a meta-analysis of 819 patients showed that a high PLR was associated with a worse overall and disease-free survival, although effect sizes and cut-off values varied markedly across studies (25). SII demonstrated prognostic value in both recurrent/metastatic TNBC (n=62) (26) and a large neoadjuvant cohort of 422 patients, whereby postoperative SII remained an independent predictor of OS (27). Composite markers combining inflammatory and nutritional domains have also been explored. For example, the Naples Prognostic Score (NPS) outperformed PNI, NLR, PLR and controlling nutritional status (CONUT) in a cohort of 223 postoperative patients with TNBC (28). However, the majority of TNBC-specific analyses remain constrained by modest sample sizes (frequently <100 patients) (26,29,30) and inconsistent findings across cohorts. For example, PLR has only exhibited OS values considered to be borderline statistically significant before sensitivity adjustment, with numerous neoadjuvant studies having reported that SII, system inflammation response index (SIRI) and PLR were not consistently associated with treatment response or long-term outcomes. Given that the majority of indices quantify inflammatory activation or nutritional reserve in isolation, these values fail to capture bidirectional interactions, which are particularly relevant in TNBC, whereby systemic inflammation, lymphocyte depletion and metabolic fragility often coexist. These limitations highlight the need for a simple integrative biomarker capable of concurrently reflecting inflammatory-immune activity and nutritional status to improve preoperative risk stratification in TNBC.
To address this gap, the present study has developed the lymphocyte-albumin-monocyte index (LANI), a novel biomarker combining serum albumin (ALB) and the lymphocyte-to-monocyte ratio (LMR). Both parameters are routinely measured and inexpensive, supporting feasibility for clinical use. ALB reflects protein nutritional status, as well as the inflammatory response of the host, as hypoalbuminemia is associated with cytokine-driven catabolism, impaired hepatic synthesis and poor tolerance to treatment (31,32). LMR represents the balance between antitumor immunity and tumor-promoting inflammation, as lymphocytes mediate cytotoxic surveillance (33), whereas monocytes can differentiate into tumor-associated macrophages that foster invasion and immune escape (34). In TNBC, accumulating evidence has demonstrated the pronounced coexistence of immune suppression and metabolic exhaustion. Clinically, patients with TNBC frequently exhibit elevated systemic inflammatory activation and impaired lymphocyte-mediated immunity. High NLR has been repeatedly associated with reduced disease-free and OS in early-stage and neoadjuvant TNBC cohorts (35–37), while SII has been identified as an independent adverse prognostic factor in recurrent/metastatic TNBC and in pre-surgery assessments of patients who have undergone neoadjuvant treatment (38). Beyond peripheral inflammation, studies assessing tumor-infiltrating lymphocytes have revealed that increased NLR is associated with lower tumor-infiltrating lymphocyte (TIL) density and an unfavorable CD8/Foxp3 ratio, reflecting a shift toward an immunosuppressive microenvironment (26,39). These findings collectively indicate that TNBC is characterized by both systemic lymphocyte depletion and heightened myeloid-driven inflammatory activity, features that contribute to immune dysfunction and metabolic vulnerability. Existing single-dimension inflammatory or nutritional markers capture only certain aspects of this biology and are therefore insufficient to reflect the dual immune-metabolic disturbance typical of TNBC.
The present study aimed to evaluate the prognostic importance of preoperative LANI in surgically treated TNBC and develop a LANI-based nomogram for individualized survival prediction. A retrospective cohort of 166 patients was analyzed to assess the association between preoperative LANI and long-term OS. Kaplan-Meier curves and multivariate Cox models were applied to determine its prognostic value and a nomogram incorporating LANI, tumor (T) stage and histologic grade was constructed for personalized prediction. Model performance was examined using time-dependent receiver operating characteristic (ROC) curves, calibration plots, Brier scores and decision curve analysis (DCA). Overall, LANI, in addition to its statistical performance, relies on two inexpensive, readily available parameters, highlighting its potential as a practical biomarker for preoperative risk assessment, treatment planning and longitudinal monitoring in TNBC.
Discussion
Within the present study, the LANI model, an integrative biomarker combining serum ALB and the LMR, was developed. Furthermore, its strong prognostic value in TNBC was demonstrated. Among 166 surgically treated patients, those with LANI=2 (ALB ≥40.0 g/l and LMR ≥2.97) consistently showed the most favorable OS. Multivariate Cox regression demonstrated LANI as an independent protective factor, whereas higher T stage (T3-T4) and poor histologic differentiation (G3) were adverse prognostic indicators. A prognostic nomogram incorporating LANI, T stage and histologic grade achieved robust discrimination, reliable calibration and clear clinical net benefits, highlighting its translational potential. The LANI thresholds were derived from ROC-based cut-off values and rounded to commonly used clinical reference points to enhance interpretability without impairing predictive performance.
Beyond statistical performance, the biological foundation of LANI provides a coherent mechanistic explanation for its prognostic relevance in TNBC. In this cohort, low serum ALB was significantly associated with higher nodal burden, a more advanced AJCC stage and worse histologic differentiation, whereas a reduced LMR was associated with deeper primary tumor invasion. These clinical patterns suggest that an unfavorable LANI profile reflects not only anatomical tumor advancement but also a profoundly perturbed host milieu characterized by chronic inflammation, metabolic stress and compromised antitumor immunity.
Serum ALB is a sensitive indicator of protein-energy reserve and inflammatory-metabolic load, whereby in aggressive breast cancer types, proinflammatory cytokines, such as IL-6 and TNF-α, are frequently elevated and activate STAT3 and NF-κB signaling in hepatocytes, shifting protein synthesis toward acute-phase reactants at the expense of ALB production (42–44). This negative acute-phase response accelerates proteolysis, amplifies oxidative stress and sustains a systemic catabolic state, consistent with studies showing that ALB-related inflammatory ratios, such as the neutrophil percentage-to-ALB ratio (NPAR), reflect systemic inflammation and distant metastatic potential in breast cancer (45–47). Meanwhile, the LMR captures the balance between lymphocyte-mediated antitumor immunity and monocyte/macrophage-driven protumor inflammation. Accumulating evidence has shown that breast cancer cells promote monocyte differentiation into M2-polarized tumor-associated macrophages through exosomal long non-coding RNAs, the MIR4435-2HG/ubiquitin-conjugating enzyme E2 N axis and the leupaxin/histone deacetylase 6/early growth response 2 pathway, accompanied by upregulation of IL-10, VEGF and TGF-β, thereby facilitating angiogenesis, epithelial-mesenchymal transition and immune escape (48–50). Integration of these findings with the present results suggests LANI effectively unifies two key biological axes, protein-energy reserve and immune-cell homeostasis, into a condensed surrogate of the host immunometabolic state, providing a robust mechanistic basis for its association with TNBC clinical outcomes.
Growing evidence has indicated that inflammatory-nutritional composite indices exhibit improved prognostic discrimination compared with single inflammatory markers in breast cancer. For example, in a postoperative TNBC cohort (n=223), the NPS demonstrated higher AUCs and C-indices compared with PNI, NLR, PLR and CONUT for both OS and breast cancer-specific survival, underscoring the value of integrating immune and nutritional dimensions (28). In a neoadjuvant TNBC population, Zhu et al (30) showed that a multiparametric model incorporating IL-6, PLR, SII and Ki-67 exhibited improved stratification of disease-free survival compared with any single indicator. Consistently, Sun et al (38) introduced the ALB-corrected NLR ratio (NLR-0.04 × ALB), reporting C-indices of 0.74-0.76 for disease-free survival and OS in both the training and validation cohorts, outperforming traditional inflammation-based parameters. Furthermore, a large neoadjuvant study demonstrated that pretreatment and posttreatment NLR markedly contributed to OS prediction, with the constructed nomogram reaching a C-index of ~0.76, further supporting the rationale for embedding inflammatory markers into composite prognostic models (51).
Based upon these breast cancer-specific findings, the present study introduced a simple TNBC-focused composite index (LANI) that integrates serum ALB and the LMR into a single prognostic measure and to the best of our knowledge, this was applied for the first time in tumor prognostic research. In the present cohort, preoperative LANI achieved an AUC of 0.792 for OS, outperforming ALB alone (AUC=0.757) and the LMR alone (AUC=0.634). Previous breast cancer studies have shown that commonly used inflammatory or inflammatory-nutritional markers, such as NLR, SII, and SIRI, typically yield AUC values between 0.58-0.63, whereas composite scores such as NPS, PLR or NLR-based prognostic models frequently fall between 0.60-0.70 (28,52,53). Within this framework, the AUC=0.792 of LANI lies toward the upper end of the performance spectrum reported for similar indices and reflects a comparatively strong discriminatory ability in the TNBC setting. Although isolated studies have described higher AUCs, such as an NLR AUC=0.827 in an overall breast cancer population (54), these findings were influenced by differences in study population and the incorporation of tumor markers, limiting direct comparison. Collectively, these observations position LANI as a high-performing, biologically grounded inflammatory-nutritional index with potential utility for prognostic refinement in TNBC.
Although neutrophil, lymphocyte, monocyte, platelet and ALB values were available for all patients in the present study, a number of biochemical indicators required for reconstructing mGPS, PNI or CONUT, specifically C-reactive protein, total protein and total cholesterol, were not consistently documented. As the present study was retrospective and relied entirely on electronic medical records, these parameters were only obtained when clinicians suspected inflammatory activity or metabolic-nutritional abnormalities, resulting in marked missingness and precluding reconstruction of those indices. Despite this limitation, the prognostic performance of LANI remained comparable with and in some instances higher than that reported for established inflammatory-nutritional markers, suggesting the potential advantages of integrating immune and nutritional components into a unified index. As LANI was newly introduced in the present study, its prognostic utility has not been evaluated previously in breast cancer or other malignancies. Future prospective TNBC cohorts with complete biochemical datasets will be key in reconstructing established indices and enabling direct, head-to-head comparisons of ROC-based and C-index performances to precisely determine the clinical positioning of LANI.
By jointly incorporating serum ALB and the LMR, LANI consolidates nutritional and immune status into a quantitative surrogate of immunometabolic exhaustion. Patients with LANI=0, defined by concurrent hypoalbuminemia and low LMR, exhibit a high-risk host phenotype marked by chronic inflammation, catabolic metabolic remodeling, lymphocyte depletion and myeloid-dominant immunosuppression. This phenotype aligns with recent studies demonstrating that ALB-based inflammatory ratios and lymphocyte-derived indices (including NPAR and PLR) predict distant metastasis and unfavorable survival in breast cancer (50,55). In TNBC, such immunometabolic exhaustion frequently coexists with an immunosuppressive tumor microenvironment characterized by M2-type macrophage enrichment, insufficient CD8+ T-cell infiltration and elevated expression of checkpoint molecules including programmed cell death protein 1/programmed death-ligand 1, T cell immunoglobulin and mucin domain-containing 3 and lymphocyte activation gene 3, all of which promote immune evasion and diminish therapeutic benefit (56–59). Inflammatory cytokines, tumor-infiltrating lymphocytes and immune checkpoint molecules were not analyzed in the present study, as owing to the retrospective design, such measurements were not part of the routine assessment at the time of patient enrollment. Consequently, long-term archived serum or tissue specimens suitable for multiplex cytokine testing or immune profiling were not consistently available, precluding reliable quantification of these biomarkers. Nevertheless, the clinical patterns observed in the present cohort, including the significantly worse OS in patients with low LANI and its association with more advanced clinicopathological features, are consistent with established translational evidence suggesting that IL-6/TNF-α-driven inflammation, M2 macrophage polarization and CD8+ T-cell dysfunction shape an immunosuppressive TNBC microenvironment and contribute to adverse outcomes (60). These consistencies suggest that LANI may capture an underlying immunometabolic program integral to tumor aggressiveness and treatment responsiveness. Future investigations should therefore aim to incorporate LANI-stratified immune analyses, including: i) Multiplex immunohistochemistry to assess CD8, CD68 and CD163 expression and characterize TIL density and tumor-associated macrophage polarization; ii) serum multiplex cytokine profiling of IL-6, TNF-α and IL-10; and iii) single-cell or spatial transcriptomic profiling to delineate immunometabolic niches across LANI groups (61–63). Through such integrative approaches, LANI may evolve from a pragmatic clinical index into a translational bridge associating routine hematologic markers with high-dimensional immune-molecular phenotyping, supporting its development as a mechanistically grounded prognostic and potentially predictive biomarker in TNBC.
In addition, a number of methodological considerations should be acknowledged when interpreting the present findings. The present study was retrospective and single-center in design, with a modest sample size and a relatively limited number of outcome events, which inherently restricts the generalizability of the results. Although internal validation supported the stability of the model, the absence of external, multicenter validation precludes a full assessment of its reproducibility and robustness in broader TNBC populations. Furthermore, despite multivariable adjustment, residual confounding cannot be fully excluded, particularly because comorbidities, inflammatory conditions and medication exposures that could influence ALB, lymphocyte or monocyte measurements were not systematically documented. More specifically, serum ALB may be influenced by unrecognized hepatic dysfunction (including steatosis, chronic hepatitis or impaired synthetic capacity), renal protein loss, inflammatory cytokine-driven acute-phase responses, perioperative hemodilution from intravenous fluids, malnutrition, catabolic illness and less commonly, protein-losing enteropathy (64,65). In addition, lymphocyte and monocyte counts may fluctuate with acute or chronic infections, autoimmune or inflammatory disorders, hematologic abnormalities, physiologic stress responses and prior or undocumented exposure to immunosuppressive medications or corticosteroids. Given that such factors were not consistently captured in the present retrospective dataset, their potential confounding effects could not be fully assessed. Furthermore, although G2 tumors exhibited an intermediate risk in the multivariate analysis, the modest effect size and limited number of events necessitate cautious interpretation and further validation in larger cohorts. Similarly, the low HR observed in the LANI=2 subgroup must be viewed in the context of event sparsity, as only a single mortality occurred within this category in each cohort, which inevitably broadened the CIs, reflecting statistical limitations rather than model instability. Despite this, the protective direction of association remained consistent across all cohorts and sensitivity analyses, supporting the biological plausibility of LANI as an indicator of host resilience. The integrated nomogram combining LANI, T stage and histologic grade demonstrated strong discrimination, favorable calibration and meaningful clinical utility, yet these prognostic properties also require validation in larger, more event-rich populations. Collectively, these sources of bias are likely non-differential in nature and would tend to attenuate, rather than exaggerate, the observed associations, suggesting that the estimated effect of LANI may, if anything, be conservative.
Future prospective, large-scale, multicenter studies with standardized documentation of comorbidities, inflammatory and nutritional biomarkers and medication exposures will be key in validating these findings across heterogeneous TNBC populations. Incorporating serial measurements will allow characterization of dynamic immuno-nutritional trajectories throughout the perioperative period and adjuvant therapy. Further integration of LANI with TNBC molecular subtyping, genomic and immunogenomic features and emerging multi-omics signatures, may deepen understanding of the immunometabolic mechanisms underlying host-tumor interactions. Embedding LANI into clinical prediction models or digital decision-support platforms may ultimately enhance individualized risk stratification and guide perioperative and systemic treatment planning within precision oncology frameworks. Overall, LANI represents a simple, accessible and biologically grounded biomarker with promising utility in the preoperative evaluation of TNBC, warranting further validation and clinical translation in future multicenter prospective studies.
In conclusion, the present study demonstrates that the LANI, derived from serum ALB and the LMR, is a reliable and independent predictor of OS in patients with TNBC. LANI reflects the combined influence of nutritional status and systemic immune-inflammatory balance, enabling clearer preoperative risk stratification compared with either component alone. The LANI-based nomogram showed strong discrimination, good calibration and meaningful clinical benefits in both the training and validation cohorts. These findings support LANI as a simple and reproducible tool that may complement conventional pathological parameters and assist individualized perioperative management of TNBC.