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Ismaili N. Evolving landscape of biomarkers in colorectal cancer: From interleukin-8 to integrated multi-marker strategies. World J Gastrointest Surg 2026; 18(10): 120555 [DOI: 10.4240/wjgs.120555]
Nabil Ismaili, Department of Medical Oncology, Mohammed VI Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Mohammed VI Foundation of Sciences and Health (FM6SS), Casablanca 82403, Casablanca-Settat, Morocco
Author contributions: Ismaili N was responsible for conceptualization, methodology, and software validation, formal analysis and investigation, resources, data curation, writing original draft, review and editing, and visualization.
AI contribution statement: We acknowledge the use of generative AI in drafting this manuscript and assume full responsibility for its content. Our usage was limited to DeepSeek and Grammarly for editing and readability, while explicitly excluding ChatGPT and Notebook LM. AI played no role in data handling, analysis, or scientific rationale.
Conflict-of-interest statement: The author reports no relevant conflicts of interest for this article.
Corresponding author: Nabil Ismaili, Chairman, Chief Pharmacist, Professor, Department of Medical Oncology, Mohammed VI Faculty of Medicine, Mohammed VI University of Sciences and Health (UM6SS), Mohammed VI Foundation of Sciences and Health (FM6SS), Mohammed Taïeb Naciri Street, Anfa City, Hay Hassan Municipality, Casablanca 82403, Casablanca-Settat, Morocco. nismaili@um6ss.ma
Received: March 3, 2026 Revised: March 18, 2026 Accepted: August 28, 2026 Published online: October 27, 2026 Processing time: 231 Days and 23.1 Hours
Abstract
Interleukin-8 (IL-8) is a pro-inflammatory protein implicated in blood vessel formation, tumor growth, and cancer spread, making it a candidate biomarker in colorectal cancer (CRC). Recent prospective data confirm that serum IL-8 levels are significantly elevated in patients with CRC compared with healthy controls, with moderate diagnostic accuracy (area under the curve, 0.68) and independent predictive value. However, these findings must be interpreted within the contemporary multi-pillar biomarker framework for CRC, where mismatch repair status, RAS/BRAF mutations, tumor laterality, human epidermal growth factor receptor 2 amplification, neurotrophic tyrosine receptor kinase fusions, phosphoinositide 3-kinase pathway alterations, perioperative carcinoembryonic antigen, and postoperative circulating tumor DNA have emerged as key clinically relevant biomarkers with growing levels of evidence. This opinion review critically examines the potential role of Interleukin-8 (IL-8) within this evolving landscape and provides a comprehensive overview of the current biomarker spectrum in CRC. Although IL-8 is consistently overexpressed in CRC and shows promise in multivariable models, substantial heterogeneity in study design, assay platforms, and patient populations limits the generalizability of existing data. IL-8 may represent an investigational complementary biomarker with potential utility in enhancing diagnostic sensitivity in selected subgroups such as carcinoembryonic antigen-negative tumors; however, no prospective study has yet demonstrated a clear incremental clinical benefit when IL-8 is added to established biomarkers. Future research should focus on analytical standardization, prospective multicenter validation, integration into multi-marker algorithms, and exploration of the therapeutic potential of the IL-8/C-X-C motif chemokine receptor 2 axis.
Core Tip: Serum interleukin-8 (IL-8) levels are significantly elevated in patients with colorectal cancer and demonstrate moderate diagnostic accuracy (area under the curve, 0.68). Given this modest discriminatory performance and the absence of external validation, IL-8 does not currently meet the criteria for clinical implementation as a standalone diagnostic biomarker. Although IL-8 has shown independent associations in multivariate analyses, its clinical role remains investigational. Within the evolving biomarker landscape, where mismatch repair status, perioperative carcinoembryonic antigen, and postoperative circulating tumor DNA currently have stronger supportive evidence, IL-8 should be regarded as an investigational biomarker requiring prospective validation before clinical integration. No study to date has demonstrated that IL-8-guided strategies improve clinical outcomes in patients with colorectal cancer.
Citation: Ismaili N. Evolving landscape of biomarkers in colorectal cancer: From interleukin-8 to integrated multi-marker strategies. World J Gastrointest Surg 2026; 18(10): 120555
Colorectal cancer (CRC) represents the third most commonly diagnosed cancer and the second leading cause of cancer-related death worldwide[1]. Despite screening, and treatment advances in screening and treatment, the high mortality rate is largely attributable to late-stage diagnosis and suboptimal postoperative risk stratification after curative-intent surgery[2]. The past decade has witnessed a paradigm shift from single-molecule biomarkers toward integrated, multi-platform approaches that better capture the biological complexity of CRC[3]. Within this evolving ecosystem, circulating biomarkers have garnered particular attention due to their minimally invasive nature and potential for serial monitoring[4,5].
The spectrum of clinically relevant biomarkers in CRC has expanded considerably beyond traditional markers. Beyond the well-established role of carcinoembryonic antigen (CEA) and mismatch repair (MMR) status, molecular profiling now encompasses RAS and BRAF mutations, tumor laterality, and emerging markers such as human epidermal growth factor receptor 2 (HER2) amplification and neurotrophic tyrosine receptor kinase (NTRK) fusions. In parallel, circulating tumor DNA (ctDNA) has emerged as a powerful tool for minimal residual disease detection and treatment monitoring[6-10].
Among the myriad of investigated circulating factors, interleukin-8 (IL-8) has emerged as a molecule of considerable interest. IL-8 is a pro-inflammatory chemokine that plays a pivotal role in neutrophil recruitment and immune regulation[11]. Beyond its canonical functions in inflammation, IL-8 has been implicated in carcinogenesis through promotion of angiogenesis, cellular proliferation, and metastasis[12,13]. In CRC specifically, preclinical and clinical studies have linked IL-8 to tumor progression and metastatic potential, though its diagnostic utility as a non-invasive serum biomarker remains controversial, with conflicting findings across different populations[14,15].
Recent prospective data have added to this body of evidence, demonstrating significantly elevated serum IL-8 levels in CRC patients compared to healthy controls, with moderate diagnostic accuracy and independent predictive value[16]. However, these findings must be interpreted within the broader context of an increasingly complex biomarker landscape. Contemporary CRC management increasingly recognizes that no single biomarker can capture the disease‘s full biological complexity[17-19]. Instead, a multi-layered strategy has emerged, integrating established biomarkers, including MMR status, perioperative CEA, and emerging markers such as postoperative ctDNA, each with varying levels of evidence and clinical utility.
These observations invite a broader discussion regarding the potential role of IL-8 within this evolving framework. How should IL-8 be interpreted alongside established biomarkers, and what realistic clinical role might emerge from the cumulative evidence? This opinion review critically examines the biological rationale for IL-8 in CRC, synthesizes the current evidence regarding its diagnostic, prognostic, and predictive potential, and positions IL-8 within the contemporary multi-pillar biomarker ecosystem. We also provide a comprehensive overview of the current biomarker landscape in CRC, including RAS/BRAF mutations, tumor laterality, HER2 amplification, NTRK fusions, and phosphoinositide 3-kinase (PI3K) pathway alterations, and propose an integrated framework for biomarker-guided decision-making. We also discuss the substantial evidence gaps that remain and propose a structured roadmap for future investigation, emphasizing the need for analytical standardization, prospective validation, and demonstration of clinical utility before IL-8 can be considered for integration into evidence-based practice.
INTERLEUKIN-8: BIOLOGICAL RATIONALE AND DIAGNOSTIC PERFORMANCE
IL-8 (C-X-C motif chemokine ligand 8), a pro-inflammatory chemokine of the CXC family, plays pivotal roles in neutrophil recruitment and immune regulation[12]. Beyond its canonical functions in inflammation, IL-8 has been implicated in carcinogenesis through promotion of angiogenesis, cellular proliferation, and metastasis[13,14]. It is a key mediator of the bidirectional crosstalk between tumor and stromal cells, acting as a chemoattractant for neutrophils and myeloid-derived suppressor cells that contribute to an immunosuppressive tumor microenvironment[11,15]. Elevated IL-8 expression has been documented across multiple malignancies, including gastric, breast, and lung cancers, where it correlates with aggressive disease biology and adverse outcomes[13,17].
IL-8 acts as a key mediator of the tumor microenvironment in gastrointestinal cancers, facilitating angiogenesis, immune evasion, and metastasis[18,19]. For CRC specifically, preclinical and clinical studies have linked IL-8 to tumor progression and metastatic potential, though its diagnostic role as a non-invasive serum biomarker remains controversial, with conflicting findings across different studies[20,21]. Functional studies have demonstrated that IL-8 promotes epithelial-mesenchymal transition and cancer stem cell properties, further solidifying its role in driving metastatic behavior[11].
The study by Güneş et al[16] addresses this knowledge gap through a well-designed prospective, case-control methodology. Their demonstration of significantly elevated IL-8 in CRC patients, coupled with independent predictive value in multivariate analysis, reinforces the biological plausibility of IL-8 as a tumor-associated biomarker. However, an area under the curve (AUC) of 0.68 is below the 0.80 threshold generally required for a screening test. This performance profile mirrors that of CEA, the most widely used clinical biomarker, which exhibits similarly limited sensitivity for early-stage disease detection[22].
A prior meta-analysis reported a pooled AUC of 0.92 for IL-8 in CRC detection[20]. However, these findings must be interpreted with caution. Most included studies employed case-control designs, which are inherently vulnerable to spectrum and selection biases. Such designs tend to overestimate diagnostic performance compared with prospective cohort studies or true screening settings. In addition, heterogeneity in assay platforms, variability in cutoff thresholds, and the frequent inclusion of advanced-stage tumors may have further inflated pooled estimates. A more recent systematic review by Bazzichetto et al[15] confirmed that IL-8 is overexpressed in CRC tissues, but importantly, sensitivity analysis revealed that the prognostic significance was stronger for circulating IL-8 than for tissue-detected IL-8, highlighting the importance of the sample type in interpreting results. Importantly, no large-scale prospective validation study conducted in an unselected or asymptomatic population has confirmed these high diagnostic accuracy metrics[16,20,21].
THE EVOLVING BIOMARKER LANDSCAPE: FROM SINGLE MOLECULES TO INTEGRATED STRATEGIES
Contemporary CRC management increasingly recognizes that no single biomarker can capture the disease’s full biological complexity. Instead, a multi-layered strategy has emerged, integrating established clinical biomarkers with emerging markers.
MMR status
Deficient MMR (dMMR) status has transformed therapeutic paradigms, recommended for all newly diagnosed CRC patients, dictating the class of systemic therapy (chemotherapy vs immunotherapy or chemo-immunotherapy)[23]. Patients with dMMR tumors demonstrate excellent prognosis in stage II disease, where adjuvant chemotherapy offers no benefit regardless of other risk factors[24]. The NICHE-2 trial demonstrated pathological complete response rates exceeding 65% with neoadjuvant nivolumab and ipilimumab in locally advanced dMMR colon cancer, offering a potential chemotherapy-free strategy[25,26]. Conversely, proficient MMR (pMMR) tumors require alternative risk stratification approaches.
Perioperative CEA
Despite its limitations, CEA remains the most widely used serum biomarker for postoperative surveillance in CRC[22]. Recent evidence suggests that even within the normal range (< 5 ng/mL), preoperative CEA levels ≥ 2.1 ng/mL independently predict poorer disease-free survival (DFS), with prognostic significance influenced by smoking status and tumor location. This “high-normal” CEA category may identify patients warranting closer surveillance, particularly in left-sided CRC[27].
The American Society of Clinical Oncology guidelines, while still relevant, underscore that CEA is not recommended for screening but is valuable for preoperative prognostication and postoperative surveillance, with 3-monthly testing for at least 3 years in stage II/III disease[22].
RAS/BRAF mutational status
KRAS mutations, occurring in approximately 40% of colon cancers, have long been recognized as negative prognostic factors, but their impact may not be uniform across all tumor locations. Multi-institutional studies have suggested that in non-metastatic CRC, KRAS mutation is an independent prognostic factor for worse overall survival (OS) and recurrence-free survival, specifically in left-sided tumors, whereas this association has not been consistently observed in right-sided tumors[28,29]. BRAF V600E mutations, found in 5%-10% of colon cancers, are associated with poor prognosis in microsatellite stable (MSS) tumors, although this negative impact appears attenuated in dMMR tumors[30,31].
Tumor laterality
Laterality alone is not an independent prognostic factor but rather a surrogate for underlying biology. Analyses evaluating KRAS, microsatellite instability (MSI), and laterality together have revealed a complex interaction: In patients with KRAS-mutant cancers, left-sided location has been associated with worse survival compared to right-sided location; conversely, in patients with KRAS wild-type cancers, left-sided tumors have been associated with better survival[8,32]. These findings underscore that laterality should be interpreted in conjunction with molecular markers, not as a standalone variable.
HER2 amplification and NTRK fusions
HER2 amplification occurs in approximately 3%-5% of CRC, predominantly in RAS/BRAF wild-type tumors, and represents an actionable target in the metastatic setting[33-35]. The HERACLES trial demonstrated activity of trastuzumab and lapatinib in HER2-positive metastatic CRC, and newer antibody-drug conjugates are under investigation[34,35]. NTRK fusions are rare in CRC (< 1%) but are associated with high response rates to tyrosine receptor kinase inhibitors, making routine testing recommended by guidelines despite low prevalence[36,37].
PI3K pathway alterations
The 2026 National Comprehensive Cancer Network (NCCN) guidelines recommend PI3K pathway testing for stage II-III colon cancer, including PIK3CA exon 9 and 20 mutations, as well as alterations in PIK3R1 and phosphatase and tensin homolog. For patients harboring such alterations, low-dose aspirin (100-162 mg daily for three years) is recommended as a potential secondary prevention strategy[38,39]. The mechanism by which aspirin exerts its anti-neoplastic effect may involve cyclooxygenase-2 inhibition and platelet modulation, with apparent benefit specifically in PIK3CA-mutated CRC[40,41].
In addition to tumor-related biomarkers, pharmacogenetic markers have also gained increasing clinical importance in CRC management. Screening for dihydropyrimidine dehydrogenase deficiency is now recommended before the administration of fluoropyrimidine-based chemotherapy to reduce the risk of severe or life-threatening toxicity. This example illustrates how biomarker-guided approaches are progressively extending beyond tumor biology to include treatment safety and personalization (NCCN 2026).
ctDNA
ctDNA represents one of the most promising emerging biomarkers for minimal residual disease detection; however, it is not yet incorporated into routine clinical practice and, as per NCCN 2026 guidelines, its routine use is not recommended outside of clinical trials. Multiple prospective studies have demonstrated that postoperative ctDNA detection identifies patients at ultra-high risk of recurrence (hazard ratios 6.9-14.0), with negative predictive values exceeding 90%[42-44]. The DYNAMIC-III trial and the United Kingdom TRACC Part B study provide definitive evidence that ctDNA-guided management can inform treatment intensity and de-escalation in stage II and III CRC[44-46]. Furthermore, Barault et al[47] demonstrated that a five-gene ctDNA methylation panel can monitor treatment response in metastatic CRC, with dynamics correlating with objective response and progression-free survival (PFS). The panel includes the genes EYA4, GRIA4, ITGA4, MAP3K14-AS1, and MSC. This underscores the power of epigenetic, tumor-agnostic approaches for longitudinal monitoring.
Beyond these established pillars, emerging biomarkers continue to expand the diagnostic and prognostic armamentarium. Methylation markers, including the Food and Drug Administration-approved septin 9 assay, have demonstrated excellent performance characteristics, with recent multicenter validation of the MethylDT test (NTMT1 and MAP3K14-AS1) reporting 91.2% sensitivity for CRC and 87.4% for early-stage disease. Proteomic approaches have identified novel candidates such as SET domain containing 7, which achieved an AUC of 0.947 in validation cohorts and correlated with tumor stage and microsatellite instability. Metabolomic profiling has similarly revealed distinct signatures, with four metabolites (hexadecanedioic acid, 4-dodecylbenzenesulfonic acid, 2-pyrocatechic acid, and formylanthranilic acid) demonstrating AUC values exceeding 0.70[48-50]. These examples illustrate the rapid expansion of biomarker discovery in CRC but also highlight the gap between biomarker discovery and clinical implementation.
The current landscape of validated and emerging biomarkers in CRC is summarized in Table 1.
Table 1 Key clinical trials and studies evaluating circulating biomarkers in colorectal cancer.
Biomarker
Study/trial
Population
Key findings
Level of evidence
Ref.
ctDNA (MRD detection)
DYNAMIC-III
Stage III colon cancer (n = 1002)
ctDNA-guided de-escalation reduced oxaliplatin exposure (88.6% → 34.8%) without compromising 3-year RFS in low-risk patients; non-inferiority not formally met
IL-8 was the only significant univariate prognostic factor after FDR correction (HR = 4.88); machine learning identified IL-8 and IL-2Ra for multivariate model
POSITIONING IL-8 WITHIN THE CONTEMPORARY BIOMARKER ECOSYSTEM
Given this complex and rapidly evolving landscape, where might IL-8 find its optimal niche? The findings of Güneş et al[16] suggest several potential applications, though each requires careful consideration of evidence levels and residual uncertainties. To visually conceptualize where IL-8 might fit within the current landscape, Figure 1 presents complementary frameworks. It proposes a sequential, integrated algorithm for biomarker-guided decision-making in CRC, incorporating MMR status, RAS/BRAF mutations, tumor laterality, CEA, and ctDNA alongside investigational markers such as IL-8.
Figure 1 This sequential algorithm illustrates a stepwise approach to integrating established and emerging biomarkers into clinical decision-making for colorectal cancer.
Mismatch repair status is the first and most critical step, directing patients with deficient mismatch repair tumors toward immunotherapy (neoadjuvant or adjuvant). For proficient mismatch repair/microsatellite stable tumors, RAS/BRAF mutational status and tumor laterality refine prognosis. Perioperative carcinoembryonic antigen provides additional risk stratification, with high-normal levels (≥ 2.1 ng/mL) warranting closer surveillance. Where available, postoperative circulating tumor DNA enables dynamic risk assessment and treatment adjustment, with the DYNAMIC-III trial demonstrating safe de-escalation in circulating tumor DNA-negative patients. Interleukin-8 remains investigational, with potential complementary value in selected subgroups. All decisions should be made in a multidisciplinary team context, weighing all factors. Interleukin-8 is presented as an investigational biomarker and should not be interpreted as a clinically validated marker. CRC: Colorectal cancer; MMR: Mismatch repair; dMMR: Deficient mismatch repair; pMMR: Proficient mismatch repair; MSI-H: Microsatellite instability-high; MSS: Microsatellite stable; CEA: Carcinoembryonic antigen; ctDNA: Circulating tumor DNA; IL-8: Interleukin-8.
Diagnostic applications
The moderate diagnostic accuracy of IL-8 (AUC, 0.68) precludes its use as a standalone screening tool. However, this performance profile aligns with that of established markers like CEA, which similarly exhibits limited sensitivity for early-stage disease[22]. In multivariate analysis, IL-8 remained an independent predictor after adjustment for CEA and other variables, suggesting that IL-8 may provide complementary biological information; however, whether this translates into clinically meaningful improvement in multi-marker diagnostic panels remains uncertain and has not yet been demonstrated in prospective studies[16].
Several retrospective studies suggest that combining IL-8 with CEA and vascular endothelial growth factor (VEGF) may improve diagnostic accuracy over using each marker alone. However, these findings come from small case-control studies and need confirmation in large prospective studies[51,52]. Mahboob et al[51] reported that a multiplexed immunoassay incorporating IL-8, CEA, and prolactin demonstrated excellent discrimination across Dukes’ stages A-D. Similarly, Bünger et al[51] found that an IL-8/CEA/VEGF panel reached an AUC of 0.87 for pancreatic cancer, much higher than CEA alone (AUC, 0.65).
Björkman et al[31] developed a prognostic model for CRC using a 48-multiplex biomarker panel and found that while IL-8 was the only significant univariate prognostic factor after correction for multiple testing, machine learning models suggested that IL-2Ra and IL-8 could be part of a multivariate prognostic algorithm, illustrating the potential of combining multiple biomarkers to improve risk stratification.
These observations suggest that IL-8’s optimal role, if any, would likely be as part of multi-marker models. At present, however, no prospective study has demonstrated incremental diagnostic or prognostic benefit when IL-8 is added to established biomarkers such as CEA or ctDNA. Therefore, any proposed combinatorial strategy remains hypothetical.
Prognostic stratification
The study by Güneş et al[16] found no significant link between IL-8 levels and tumor features such as T stage, N stage, overall stage, lympho-vascular invasion, perineural invasion, and MSI status. However, these results should be interpreted with caution.
The study was too small to rule out modest effects, especially in subgroup analyses (e.g., synchronous tumors, n = 3; stage I, n = 4)[16]. Also, the exclusion of stage IV patients may have reduced the range of IL-8 values, making stage-related correlations harder to detect[8,21].
Importantly, most of the available prognostic evidence originates from retrospective analyses or exploratory biomarker studies, and prospective validation in well-characterized cohorts remains limited.
Prior evidence supports IL-8’s prognostic significance. Rubie et al[21] demonstrated that IL-8 upregulation was most enhanced in synchronous and metachronous CRC liver metastases, with up to an 80-fold overexpression compared to normal tissue, strongly suggesting a link between IL-8 and metastatic potential. Ueda et al[53] showed that serum IL-6 and IL-8 levels were significantly higher in patients with liver or lung metastases, indicating their possible involvement in hematogenous metastasis. Czajka-Francuz et al[54] reported that patients with higher preoperative IL-8 levels had shorter overall and disease-free survival. Likewise, Park et al[55] found that elevated systemic IL-8 independently predicted more advanced disease and worse outcomes, even after adjusting for other inflammatory markers. Pączek et al[56] found that C-X-C motif chemokine ligand 8 levels were significantly elevated in CRC patients and correlated with tumor stage and distant metastasis, with diagnostic sensitivity and NPV higher than CEA, suggesting its utility as a marker of progression.
Genetic variations in IL-8 signaling pathways may further refine risk stratification; Lurje et al[57] found that specific IL-8 polymorphisms predicted tumor recurrence in stage III CRC patients. In a combined analysis, patients with the high-expression variants of both VEGF (C+936T) and IL-8 (T-251A) were at the greatest risk for tumor recurrence, highlighting the potential of a multi-gene approach.
A particularly intriguing question is whether IL-8 could be explored as part of exploratory models aimed at refining risk stratification, though no prospective evidence currently supports its clinical integration. In patients with normal or borderline CEA levels, elevated IL-8 might signal more aggressive tumor biology driven by inflammatory and angiogenic processes, potentially identifying a subset warranting closer surveillance or consideration of adjuvant therapy. This hypothesis requires prospective validation in adequately powered cohorts with comprehensive clinico-pathological annotation and long-term follow-up[58].
Predictive biomarker potential
Beyond diagnosis and prognosis, IL-8 has been explored as a potential predictive biomarker for certain therapeutic classes, although the current level of evidence remains preliminary. Its biological role in angiogenesis suggests potential utility for anti-angiogenic therapies. Suenaga et al. reported an association between elevated baseline IL-8 and poorer outcomes with bevacizumab-based therapy[58]. However, these findings derive from retrospective analyses with limited sample sizes and have not been validated in prospective biomarker-stratified trials. Consequently, IL-8 cannot currently be considered a clinically actionable predictive biomarker for anti-angiogenic therapy in CRC.
Emerging evidence also links IL-8 to immunotherapy response. Sanmamed et al[59] reported that lower IL-8 concentrations correlated with better outcomes in patients treated with immune checkpoint inhibitors, with dynamic changes reflecting treatment response. The biological rationale involves IL-8’s role in recruiting myeloid-derived suppressor cells and promoting an immunosuppressive tumor microenvironment. Should future studies confirm these observations, IL-8 might be explored as a complementary biomarker; however, its predictive value in CRC remains unestablished. While IL-8 dynamics have been associated with immunotherapy response in melanoma and non-small-cell lung cancer, evidence in CRC, particularly in the pMMR/MSS subgroup, remains extremely limited[60]. No prospective study has established IL-8 as a predictive biomarker for immune checkpoint inhibitors in CRC. These observations were primarily reported in melanoma and non-small-cell lung cancer, and their relevance to CRC, particularly MSS/pMMR disease, remains uncertain.
Monitoring disease dynamics
Although the short half-life of IL-8 theoretically allows dynamic monitoring, IL-8 is not tumor-specific and may be influenced by systemic inflammatory, infectious, or metabolic conditions[16]. This lack of tumor specificity fundamentally differentiates IL-8 from ctDNA and may limit its utility for minimal residual disease detection[61,62].
No longitudinal study has yet demonstrated that IL-8 kinetics predict recurrence earlier than established modalities. Fleming et al[62] showed that perioperative cfDNA trends could predict recurrence as early as 48 hours post-operatively, significantly earlier than CEA, highlighting the superior dynamic range of nucleic acid-based biomarkers for early relapse detection. Key clinical studies evaluating the role of IL-8 in CRC are summarized in Table 2.
Table 2 Current status and evidence gaps for interleukin-8 as a colorectal cancer biomarker.
The integration of IL-8 into clinical practice faces several challenges that mirror those encountered by other emerging biomarkers. Pre-analytical variables, including sample collection, processing, and storage, can significantly influence measured IL-8 concentrations and require standardization[60]. Analytical validity must be established across platforms, with attention to detection limits, reproducibility, and inter-laboratory comparability. Reference ranges need definition in diverse populations, accounting for factors such as age, sex, comorbidities, and inflammatory conditions that may confound interpretation.
Future investigations of IL-8 would benefit from a structured biomarker-development framework progressing from analytical validation to clinical utility assessment.
Phase 1: Analytical validation
Standardization of IL-8 assays across platforms, establishment of reference ranges, and definition of clinically meaningful thresholds. The current cutoff of 42.3 ng/L derived from receiver operating characteristic analysis requires validation in independent cohorts. Given the variability in assay platforms (e.g., enzyme-linked immunosorbent assay, multiplex bead assays), harmonization is critical[15].
Phase 2: Clinical validation
A particularly relevant unmet need concerns risk stratification in pMMR/MSS CRC. Although IL-8-mediated inflammatory and angiogenic pathways are biologically plausible contributors to aggressive tumor behavior, there is currently no prospective evidence demonstrating that IL-8 improves risk prediction beyond established clinicopathologic factors or ctDNA status in this population. This hypothesis warrants formal testing in adequately powered prospective cohorts[39]. Studies should also explore the additive value of IL-8 to existing composite scores like the modified Glasgow Prognostic Score or neutrophil-to-lymphocyte ratio, as suggested by Park et al[55].
Phase 3: Multi-marker integration
Development and validation of algorithm-driven models incorporating IL-8 with established biomarkers (CEA, ctDNA, methylation markers) and clinical variables[40,41]. Machine learning approaches may identify optimal combinations and weighting schemes that maximize diagnostic and prognostic accuracy. The work by Björkman et al[31] using random survival forest analysis provides a methodological template for such integration.
Phase 4: Clinical utility assessment
Randomized trials demonstrating that IL-8-guided management improves clinically meaningful endpoints (DFS, OS, or treatment de-escalation…) compared with standard care. The DYNAMIC-III trial provides an exemplary template for ctDNA, demonstrating how biomarker-directed strategies can be rigorously evaluated in prospective randomized designs[45,46].
Phase 5: Therapeutic targeting
Investigation of IL-8/C-X-C motif chemokine receptor 2 (CXCR2) axis as a therapeutic target. Several agents are in preclinical and early clinical development, aiming to disrupt pro-tumorigenic signaling, inhibit angiogenesis, reduce immunosuppression, and enhance chemotherapy and immunotherapy efficacy[63]. Preclinical studies by Lee et al[64] using IL-8 transgenic and CXCR2 knockout mouse models have validated the critical role of the IL-8/CXCR2 axis in the tumor microenvironment, showing that its absence prevents CRC growth and enhances tumor necrosis, providing a strong rationale for therapeutic targeting.
Before IL-8 can be considered for clinical implementation, three conditions must be met: Analytical standardization across platforms, external clinical validation in large prospective cohorts, and demonstration of clinical utility in randomized biomarker-guided trials. None of these thresholds has yet been achieved.
LIMITATIONS AND CAVEATS
Several limitations of the Güneş et al[16] study merit consideration when interpreting its findings and implications. The relatively small sample size (44 patients, 44 controls) may have limited statistical power, particularly for subgroup analyses examining associations with clinicopathological features. This single-center study has several limitations. First, the result may not apply to other populations, as geographic, ethnic, and dietary factors can affect inflammatory markers and cutoff values. Second, the lack of long-term follow-up precludes assessment of IL-8’s prognostic value for recurrence, metastasis, or survival, although previous studies have suggested such associations[55,57,58]. Third, single-time-point measurement precludes assessment of intra-individual variability, longitudinal kinetics, and temporal association with recurrence or treatment response. Fourth, although groups were matched for age, other factors such as hypertension or diabetes, may still have influenced the results. Finally, the findings were not validated in independent cohort, which is essential any clinical use[20].
More broadly, the current evidence base for IL-8 in CRC remains exploratory. The predominance of case-control designs, limited cohort sizes, heterogeneity of assay methods, and absence of prospective clinical utility trials preclude definitive conclusions regarding its clinical value[16,20,21].
The systematic review by Bazzichetto et al[15] underscores that while circulating IL-8 is a strong prognostic factor, the data are predominantly from retrospective or case-control studies, and prospective validation is urgently needed.
FUTURE PERSPECTIVES
The integration of multiple biomarkers into clinical practice represents both an opportunity and a challenge. Several key directions will shape the future landscape.
Refining multi-marker algorithms
The development and validation of integrated algorithms that sequentially incorporate MMR status, RAS/BRAF mutations, tumor laterality, CEA, and ctDNA will be essential. Machine learning approaches may identify optimal combinations and weighting schemes that maximize diagnostic and prognostic accuracy[58,59]. The work by Björkman et al[31] using random survival forest analysis provides a methodological template for such integration.
Standardization and harmonization
Substantial variability exists across assay platforms, cutoffs, and reporting standards for most biomarkers. International efforts to harmonize pre-analytical variables, analytical validity, and clinical interpretation are urgently needed[65]. For IL-8 specifically, standardization of enzyme-linked immunosorbent assay platforms and establishment of reference ranges across diverse populations will be critical before clinical implementation.
Prospective validation in biomarker-driven trials
The DYNAMIC-III trial provides an exemplary template for how biomarkers can be rigorously evaluated in prospective randomized designs[46]. Similar trials are needed for IL-8 and other emerging markers, testing whether biomarker-guided strategies improve clinically meaningful endpoints such as DFS, OS, and quality of life while reducing overtreatment.
Cost-effectiveness and implementation science
Real-world studies evaluating the cost-effectiveness of multi-marker testing and its impact on healthcare systems are essential. The adoption of biomarker-guided strategies must be feasible in resource-constrained settings, requiring pragmatic, stepwise approaches that prioritize tests with the highest clinical utility[40,66].
Novel technologies and biomarkers
Beyond established markers, emerging technologies including liquid biopsy multi-omics, exosomal profiling, and fragmentomics, may further refine personalized care. Malla et al[7] and Vojjala et al[66] have highlighted the practical implications and therapeutic challenges of integrating ctDNA into clinical management. For IL-8, exploration of its role as a predictive biomarker for immunotherapy, particularly in pMMR/MSS tumors, warrants further investigation[38].
Therapeutic targeting of the IL-8/CXCR2 axis
Preclinical studies by Lee et al[64] using IL-8 transgenic and CXCR2 knockout mouse models have validated the critical role of the IL-8/CXCR2 axis in the tumor microenvironment, showing that its absence prevents CRC growth and enhances tumor necrosis. Several agents targeting this axis are in early clinical development, aiming to disrupt pro-tumorigenic signaling, inhibit angiogenesis, reduce immunosuppression, and enhance chemotherapy and immunotherapy efficacy[63].
Future directions and potential strategies for integrating IL-8 into multi-marker approaches are outlined in Table 3.
Table 3 Summary of established and emerging biomarkers in colorectal cancer.
Biomarker
Prevalence
Clinical utility
Evidence level
Guideline recommendation
Ref.
MMR/MSI
15% stage II/III
Predictive for immunotherapy; prognostic in stage II
The body of evidence surrounding IL-8 in CRC has expanded considerably over the past decade, confirming that circulating IL-8 levels are significantly elevated in patients with CRC. However, the observed diagnostic performance remains modest (AUC, 0.68), and substantial heterogeneity in study design, assay platforms, and patient populations limits generalizability, with external validation in independent cohorts still lacking[16].
The contemporary biomarker landscape in CRC has evolved far beyond single molecules, now encompassing a diverse spectrum of clinically relevant markers. MMR status guides immunotherapy decisions, with the NICHE-2 trial demonstrating pathological complete response rates exceeding 65% with neoadjuvant immune checkpoint blockade in dMMR tumors[25]. RAS and BRAF mutations provide critical prognostic information, with KRAS mutation exerting differential effects depending on tumor laterality[28,31,32]. Tumor laterality itself, while not an independent prognostic factor, modulates the impact of molecular alterations and should be interpreted in conjunction with mutational status[8,34]. HER2 amplification, present in 3%-5% of CRC, represents an actionable target with proven efficacy in the metastatic setting[33-35]. NTRK fusions, though rare, are associated with high response rates to tyrosine receptor kinase inhibitors and warrant routine testing[38,39]. PI3K pathway alterations now have therapeutic implications, with NCCN guidelines recommending low-dose aspirin for patients with PIK3CA-mutated tumors as a secondary prevention strategy[38-41].
Perioperative CEA retains prognostic value, particularly when interpreted with refined cutoffs and in conjunction with clinical variables[27,48,49]. ctDNA has emerged as a transformative tool for minimal residual disease detection and treatment monitoring, with the DYNAMIC-III trial demonstrating that ctDNA-guided de-escalation reduces oxaliplatin exposure by approximately 60% with comparable oncologic outcomes[46]. Methylation markers, proteomic signatures, and metabolomic profiles continue to expand the diagnostic and prognostic armamentarium, though many await clinical validation[47-49].
Within the contemporary multi-pillar biomarker framework, where MMR status guides immunotherapy decisions, perioperative CEA informs surveillance strategies, and ctDNA enables detection of minimal residual disease, IL-8 must be positioned as an investigational marker rather than a clinically actionable tool. The biological plausibility of IL-8 in inflammation-driven tumorigenesis is well established, and retrospective studies have demonstrated associations with prognosis and metastatic potential. Nevertheless, these data do not yet meet the threshold for clinical implementation.
At present, available evidence does not support the routine use of IL-8 for diagnosis, prognostication, therapeutic selection, or disease monitoring in CRC. The critical question is not whether IL-8 holds biological relevance, it clearly does, but whether it can provide incremental clinical value beyond established biomarkers. This question remains unanswered.
Future research must prioritize a structured developmental pathway: Analytical standardization across platforms; prospective validation in large, well-characterized multicenter cohorts; integration into algorithm-driven multi-marker models; and ultimately, demonstration of clinical benefit in biomarker-guided interventional trials. Until these thresholds are met, IL-8 should remain within the domain of clinical investigation rather than clinical practice. The trajectory from exploratory biomarker to clinically useful tool is long and demanding, but for IL-8, this journey has only just begun.
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