Systemic immune-inflammation index and serum lactoferrin: A novel tool for individualized prognostic assessment in elderly colon cancer

Abstract

The global aging trend has significantly increased the incidence of colon cancer among elderly patients, who often present with complex comorbidities and frailty, challenging conventional tumor node metastasis staging. A recent prospective study demonstrated that the combination of the systemic immune-inflammation index and serum lactoferrin serves as a potent, independent prognostic tool for elderly colon cancer post-surgery. By integrating “inflammation-immunity” and “nutrition-immunity” dimensions, this combined model offers superior predictive accuracy for overall and disease-free survival compared to traditional staging. This cost-effective and minimally invasive approach holds substantial promise for postoperative risk stratification and the optimization of perioperative management in primary care and resource-limited settings. Future research should focus on multicenter validation and the integration of molecular markers to further refine individualized management strategies for this vulnerable population.

Key Words: Systemic immune-inflammation index; Serum lactoferrin; Colon cancer; Elder; Prognosis

Core Tip: This prospective study identifies elevated preoperative systemic immune-inflammation index combined with low serum lactoferrin as independent prognostic biomarkers in elderly colon cancer patients. This cost-effective and easily measurable combination reflects both systemic inflammatory burden and immune-nutritional status, enhancing traditional tumor node metastasis staging. It holds substantial potential for individualized postoperative risk stratification in routine clinical practice.

INTRODUCTION

With the continued global aging trend, the occurrence of colon cancer among elderly individuals has steadily increased, posing substantial challenges for clinical treatment and prognostic evaluation. Elderly patients frequently exhibit multiple comorbid conditions, reduced functional capacity, and weakened immune responses, which markedly influence surgical tolerance, postoperative recovery, and long-term survival outcomes[1,2]. Although the tumor node metastasis (TNM) staging system remains the primary framework for tumor prognostic assessment, it does not adequately capture important biological features in elderly patients, including systemic inflammation, immune function, and nutritional condition. Consequently, the development of simple and cost-efficient prognostic biomarkers that incorporate multidimensional information is essential for individualized therapy and precise management of elderly patients with cancer.

In recent years, markers related to inflammation, immunity, and nutrition have shown complementary roles in tumor prognosis assessment. The systemic immune-inflammation index (SII), which combines neutrophil, platelet, and lymphocyte counts, provides an integrated measure of systemic inflammatory and immune status[3]. Lactoferrin (LF), a multifunctional glycoprotein, participates in the regulation of iron metabolism and also demonstrates anti-inflammatory, antioxidant, and potential anti-tumor effects[4].

These two markers provide dynamic information from the perspectives of “inflammation-immunity” and “nutrition-immunity”, respectively. However, their combined predictive value in elderly colon cancer prognosis has not been systematically evaluated. Zhu et al[5] first explored the predictive role of SII combined with serum LF for postoperative survival in elderly colon cancer patients, providing new insights into prognostic assessment in this population.

VALUE AND VALIDATION OF THE COMBINED SII-LF MODEL

This study by Zhu et al[5] included 62 elderly patients with colon cancer (age ≥ 65 years) who received radical surgical treatment. Through dynamic assessment of perioperative blood parameters, inflammatory indices, and tumor markers, together with postoperative follow-up information, the prognostic value of SII and serum LF for overall survival (OS) and disease-free survival (DFS) was systematically analyzed. The findings indicated that elevated preoperative SII and reduced LF levels were significantly correlated with worse OS and DFS outcomes. Multivariate Cox regression analysis further confirmed that SII and LF are independent prognostic predictors beyond traditional factors such as TNM staging. Combined assessment of SII and LF improved postoperative risk stratification accuracy, with predictive performance exceeding that of the TNM staging system. These findings demonstrate clinical potential for identifying high-risk patients, guiding individualized postoperative management, and supporting adjuvant treatment decisions. The study suggests that SII and LF, as simple and cost-effective biomarkers, are promising tools for prognostic evaluation in elderly colon cancer patients. This model may also inform preoperative surgical strategies, as SII ≥ 585 combined with LF < 185 ng/mL indicates a high systemic inflammatory burden and impaired immune-nutritional status. Such patients may benefit from minimally invasive or palliative surgical approaches rather than extensive radical resection, thereby reducing surgical trauma and complication risk.

The key strength of this study lies in the innovative combination of SII and LF to construct a multidimensional prognostic assessment model. SII reflects systemic inflammatory and immune status, and its elevation often indicates a pro-inflammatory environment and suppressed anti-tumor immunity, both of which are closely associated with tumor progression and poor prognosis[3,6,7].

In colorectal cancer (CRC), neutrophils function not merely as inflammatory responders but as active facilitators of tumor progression. On one hand, they suppress anti-tumor immunity by releasing arginase-1[8], reactive oxygen species[9], and nitric oxide[10], thereby impairing CD8⁺ T-cell activity and promoting an immunosuppressive milieu[10,11]. On the other hand, neutrophils secrete pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-α, which sustain a tumor-promoting inflammatory microenvironment and drive tumor growth[12]. In addition, neutrophils can form neutrophil extracellular traps that capture circulating tumor cells (CTCs), facilitating their adhesion and colonization at distant sites, thereby promoting metastasis[13]. Their secretion of vascular endothelial growth factor and matrix metalloproteinase 9 further contributes to angiogenesis and extracellular matrix remodeling[14,15].

Platelets act as “covert accomplices” within the tumor microenvironment (TME). They can shield CTCs from immune recognition through physical cloaking[16], while releasing transforming growth factor-β to induce epithelial-mesenchymal transition, thereby enhancing tumor invasiveness and metastatic potential[17]. Moreover, interactions between platelets and endothelial cells promote tumor cell adhesion and transendothelial migration[18]. Notably, platelets may also express molecules with programmed death-ligand 1-like functions, further facilitating immune evasion through checkpoint-related mechanisms[19].

In contrast, lymphocytes-particularly T cells-represent the principal effector population mediating anti-tumor immunity in CRC[20]. CD8⁺ T cells exert direct cytotoxic effects on tumor cells and maintain immune surveillance through neoantigen recognition[21], whereas Th1 cells enhance anti-tumor responses via IFN-γ secretion and orchestrate an immune-activated TME[22]. Accordingly, lymphopenia is often indicative of impaired anti-tumor immunity and is closely associated with adverse clinical outcomes. Collectively, these findings provide a mechanistic basis for SII, in which elevated neutrophil and platelet counts coupled with reduced lymphocyte levels reflect a shift toward a pro-tumor inflammatory and immunosuppressive state (Figure 1). LF possesses antibacterial and anti-inflammatory properties, and recent studies have revealed additional anti-tumor mechanisms. These include regulation of iron homeostasis through iron-binding capacity and inhibition of tumor growth via iron chelation[4], suppression of NF-κB pathway activation through binding to TLR2 and TLR9 receptors[23], and enhancement of radiotherapy-induced oxidative stress with downregulation of DNA repair gene expression through inhibition of the NRF2 antioxidant signaling pathway, thereby promoting tumor cell death[24]. Owing to high receptor expression on CRC cells, LF has also emerged as a potential targeted drug delivery carrier, enabling receptor-mediated endocytosis and improving the stability and bioavailability of hydrophobic agents[25-28]. Dynamic monitoring in this study revealed a significant postoperative decline in LF levels, suggesting a close association with postoperative immune recovery and nutritional status. LF contributes to immune defense by limiting bacterial growth through iron sequestration[29], regulating immune cell activity[30], and promoting lymphocyte proliferation and differentiation, particularly activation of CD4⁺ T cells and NK cells[31,32]. The postoperative reduction in LF may reflect immune consumption and decreased nutritional reserves induced by surgical stress, indicating further impairment of immune function[33].

Figure 1 Synergistic role of systemic immune-inflammation index-associated immune cells in colorectal cancer progression. NEU: Neutrophil; PLT: Platelet; LYM: Lymphocyte; NO: ‌Nitric oxide; ROS: Reactive oxygen species; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; NETs: ‌Neutrophil extracellular traps; VEGF: Vascular endothelial growth factor; MMP-9: Matrix metalloproteinase 9; CTCs: Circulating tumor cells; TGF-β: Transforming growth factor-β; EMT: Epithelial-mesenchymal transition; PD-L1: Programmed death-ligand 1; IFN-γ: ‌Interferon-gamma; TME: Tumor microenvironment‌; MDSCs: Myeloid-derived suppressor cells; TAM: Tumor-associated macrophage; CAF: Cancer-associated fibroblasts; MMPs: Matrix metalloproteinases; SII: Systemic immune-inflammation index.

To further contextualize the findings by Zhu et al[5], we summarize recent representative studies investigating the prognostic or biological relevance of SII and LF in CRC (Table 1)[25,27,34-58].

Table 1 Representative studies on systemic immune-inflammation index and lactoferrin in colorectal cancer (2020-2026).

Parameter	Ref.	Research type	Test set	Key findings
SII	Sato et al[34]	Retrospective study	86 patients	In patients with obstructive CRC, lower preoperative SII was independently associated with poorer RFS
	Hernandez-Ainsa et al[35]	Retrospective study	428 patients	SII levels were significantly elevated in CRC patients and varied with disease progression, suggesting its potential as an adjunct tool for early diagnosis
	Feier et al[36]	Retrospective study	296 patients	SII levels were significantly higher in colon cancer than in rectal cancer, indicating distinct systemic inflammatory response patterns between these tumor types
	Rimini et al[37]	Prospective study	3810 patients	SII was identified as an independent inflammatory biomarker predicting cancer risk in the general population, including CRC
	Feng et al[38]	Retrospective study	342 patients	SII levels were significantly higher in CRC compared with adenomatous polyps, demonstrating its utility in distinguishing early-stage cancer from benign adenomas
	Polk et al[39]	Retrospective study	170 patients	In colon cancer liver metastases, low SII predicted longer RFS; whereas in rectal cancer liver metastases, high SII independently predicted longer RFS and OS
	Murray et al[40]	Prospective study	181 patients	Elevated SII levels were significantly associated with more aggressive CTC-positive subtypes and poorer prognosis
	Passardi et al[41]	Prospective study	182 patients	High SII was an independent predictor of poor prognosis in metastatic CRC patients treated with chemotherapy plus bevacizumab
	Ma et al[42]	Retrospective study	248 patients	High SII was one of the independent risk factors for postoperative complications in stage II-III colon cancer patients
	Miyamoto et al[43]	Retrospective study	272 patients	The prognostic value of SII in metastatic CRC was influenced by KRAS status: Predictive for OS in KRAS wild-type patients but limited in KRAS-mutant patients
	Zeynelgil et al[44]	Retrospective study	155 patients	Low SII levels were associated with better OS in univariate analysis among metastatic CRC patients
	Wu et al[45]	Retrospective study	344 patients	The combination of SII and ferritin effectively predicted OS after curative surgery for colon cancer
	Zhang et al[46]	Retrospective study	188 patients	SII was an independent predictor of DFS after curative surgery for colon cancer, with high SII indicating poorer prognosis
	Chang et al[47]	Retrospective study	768 patients	In stage II colon cancer patients without adjuvant chemotherapy, SII levels differed significantly between left- and right-sided tumors
	Silaghi et al[48]	Retrospective study	219 patients	In emergency CRC surgery, elevated preoperative SII was associated with a higher risk of severe postoperative complications
LF	Liu et al[49]	Basic study	8 mice	In an AOM/DSS-induced mouse model of colitis-associated CRC, LF exerted both anti-inflammatory and anti-tumor effects
	Tanaka et al[50]	Interventional preclinical study	63 mice	Oral bLF significantly alleviated intestinal inflammation and improved histological injury in an AOM/DSS-induced model
	Elmorshedy et al[51]	Preclinical experimental study	50 mice	LF served as a targeting ligand in engineered NIMDs for oral colon-targeted delivery of docetaxel and atorvastatin, enhancing anti-CRC efficacy and inhibiting key pathways (p-AKT/p-ERK1/2/NF-κB)
	Elhamid et al[25]	Preclinical experimental study	120 mice	LF acted as a natural targeting ligand and drug carrier in a temperature/pH dual-responsive nanostructured microsphere system, enabling colon-targeted delivery of mesalazine and resveratrol, enhancing therapeutic efficacy and inducing tumor apoptosis
	Raval et al[27]	Basic study	63 rats	LF functioned as an efficient targeting ligand by binding to overexpressed lactoferrin receptors on cancer cells, enabling specific drug delivery and reducing systemic toxicity
	Li et al[52]	Basic study	130 mice	LF inhibited CRC progression under hyperglycemic conditions by targeting the WTAP/m6A/NT5DC3/HKDC1 axis
	Yang et al[53]	Basic study	29 mice	LF was used to trigger responsive aggregation and targeted delivery in an oral Ast delivery system, improving therapeutic effects in IBD
	Wei et al[54]	Basic study	-	Modulation of LF release rate in the colon via nanofiber carriers showed that faster release led to stronger inhibition of HCT116 CRC cells proliferation
	Bhattacharya et al[55]	Basic study	-	LF-modified nanoparticles enabled targeted delivery of methotrexate to CRC cells, enhancing antitumor efficacy and reducing systemic toxicity
	Upasana et al[56]	Basic study	36 rats	LF-functionalized nanoparticles specifically recognized CRC cells, improving targeted delivery and therapeutic efficacy of lapatinib while reducing systemic toxicity
	Ramírez-Sánchez et al[57]	Basic study	-	The anti-CRC activity of bLF depended on its glycosylation structure, inhibiting tumor growth via EGFR and ERK/Akt pathways; deglycosylation markedly reduced this effect
	Chen et al[58]	Basic study	3 samples	LF promoted the initiation and progression of LCC by activating the PI3K/AKT signaling pathway

SII: Systemic immune-inflammation index; LF: Lactoferrin; CRC: Colorectal cancer; RFS: Recurrence-free survival; OS: Overall survival; CTC: Circulating tumor cell; KRAS: Kirsten rat sarcoma viral oncogene; DFS: Disease-free survival; AOM: Azoxymethane; DSS: Dextarn sodium suipate; bLF: Bovine lactoferrin; NIMDs: Nano-in-micro delivery systems; IBD: Inflammatory bowel disease; Ast: Astaxanthin; EGFR: Epidermal growth factor receptor; LCC: Left-sided colon cancer.

The SII-LF model integrates biological information from two complementary dimensions: Systemic inflammatory burden and local immune-nutritional microenvironment. Incorporation of this model into clinical workflows may directly influence perioperative decision-making. Preoperative identification of high-risk patients (e.g., SII ≥ 585 and LF < 185 ng/mL) can support comprehensive physiological evaluation and multidisciplinary discussion, including pre-habilitation strategies. Intraoperatively, it may guide the selection of less invasive surgical approaches or enhanced supportive measures. Postoperatively, dynamic monitoring of SII and LF may help identify patients at increased risk of complications, allowing earlier intervention and treatment adjustment (Figure 2).

Figure 2 Clinical workflow of systemic immune-inflammation index-lactoferrin-guided perioperative management in elder colon cancer. SII: Systemic immune-inflammation index; LF: Lactoferrin; MDT: Multidisciplinary team.

From a clinical implementation perspective, SII and serum LF testing offer clear economic and operational advantages. Compared with costly molecular markers such as circulating tumor DNA or frequent imaging follow-up, this model provides favorable cost-effectiveness and simple testing suitable for routine and dynamic monitoring during outpatient care and postoperative follow-up. These features support broader applicability, particularly in primary hospitals and resource-limited settings, facilitating individualized management for elderly colon cancer patients.

Nevertheless, several limitations should be acknowledged in this study. The relatively small sample size (n = 62) and the single-center setting may lead to selection bias and reduce the general applicability of the findings. In addition, the maximum follow-up period of 18 months is inadequate for assessing long-term survival outcomes. Detailed evaluation of the relationships between dynamic variations in SII and LF and specific postoperative complications, such as infection or anastomotic leakage, as well as recurrence patterns, was not performed. Moreover, modern molecular classification systems, including microsatellite instability and RAS/RAF mutation status, and liquid biopsy indicators, such as circulating tumor DNA, were not incorporated. These limitations may partially constrain the overall clinical relevance and general utility of the proposed model.

RESEARCH IMPLICATIONS AND FUTURE DIRECTIONS

In the context of elderly patients with CRC, the processes of diagnosis, treatment decision-making, and prognostic evaluation are considerably more challenging due to a combination of factors, including frailty, compromised immune function, poor nutritional status, and a high burden of comorbidities. Multiple studies have confirmed that frailty is strongly associated with poor prognosis in this population[59-63]. Furthermore, compared with younger patients, the five-year survival of elderly patients is influenced not only by TNM stage but also by the presence of comorbidities, which are particularly prevalent in this age group, thereby adding further complexity to their clinical management[64]. Nutritional and immune status have also been established as critical predictors of prognosis in elderly CRC patients[65,66]. For instance, one study integrated lymphocyte subsets (LS) with the geriatric nutritional risk index (GNRI) to construct a composite biomarker (LS-GNRI), which demonstrated strong independent predictive value for OS and DFS in elderly CRC patients[67]. Although elderly patients are frequently excluded from clinical trials due to frailty and other age-related factors, accumulating evidence supports the feasibility of individualized treatment approaches in this population[68-70]. Yeo and Voutsadakis[71] reported that although patients aged over 80 years were less likely to receive systemic therapy, individualized treatment based on performance status, comorbidities, and life expectancy remains feasible, with a similar incidence of chemotherapy-related adverse events compared with younger patients. Moreover, Ketelaers et al[69] found that the geriatric-8 screening tool identified frailty in 43.5% of patients aged 70 years and older, and its integration with the comprehensive geriatric assessment (CGA) may facilitate more tailored treatment decisions. To address the substantial heterogeneity in prognosis among elderly patients, various novel predictive tools have been developed in recent years[72-74]. By integrating CGA, frailty screening, nutritional monitoring, and individualized treatment strategies, these tools hold promise for improving clinical outcomes while ensuring safety in this vulnerable population.

This study by Zhu et al[5] proposes a novel and cost-effective biomarker combination for postoperative prognostic assessment in elderly colon cancer patients, demonstrating promising clinical application potential. As summarized in Table 1, accumulating evidence supports the prognostic value of SII across multiple solid tumors, while LF is increasingly recognized for its immunomodulatory and iron-regulatory functions. Nevertheless, most existing studies remain limited by their single-center design and lack of integration with multidimensional markers. Future work should validate the predictive performance of this model through large-sample, multicenter, prospective cohorts and extend follow-up periods to confirm its long-term prognostic value. In addition, combining SII and LF with emerging molecular markers or radiomic features may help construct a more precise multidimensional prognostic stratification system.

At the mechanistic level, the systemic inflammatory state represented by high SII and the weakened local immune defense associated with LF deficiency may form a mutually reinforcing vicious cycle. Insufficient LF may exacerbate the local inflammatory TME, while chronic inflammation may further deplete LF, disrupt iron metabolism, and increase oxidative stress, collectively driving tumor progression[4,23,75]. Therefore, further exploration of the interaction between SII and LF-for example, whether LF influences SII by modulating neutrophil function or platelet activity, and how its immunomodulatory effects relate to lymphocyte subset dynamics-would deepen understanding of the tumor immune microenvironment and may provide a basis for developing comprehensive intervention strategies targeting the inflammation-immunity-nutrition axis.

In terms of clinical translation, combined SII and LF testing may become a routine auxiliary tool in the postoperative management of elderly colon cancer patients, guiding adjuvant treatment decisions, identifying high-risk individuals, and enabling longitudinal monitoring of treatment response. In addition, the application of LF as a natural dietary component or as a drug delivery carrier in cancer prevention and adjuvant therapy warrants further investigation.

CONCLUSION

The study by Zhu et al[5] preliminarily confirms the independent value of SII combined with serum LF in predicting postoperative survival in elderly colon cancer patients, providing a new perspective for individualized prognostic assessment in this population. This model shows potential for integration into existing surgical workflows and may serve as an auxiliary tool for preoperative evaluation, intraoperative decision making, and postoperative follow-up, with particular advantages in primary care and resource-limited settings. Although validation in larger cohorts and deeper mechanistic studies are still required, this work adds a valuable tool for the precise management of elderly colon cancer patients, with clear clinical relevance and translational potential.