Evolving landscape of biomarkers in colorectal cancer: From interleukin-8 to integrated multi-marker strategies

Table 2 Current status and evidence gaps for interleukin-8 as a colorectal cancer biomarker

Application	Current evidence level	Key findings	Evidence gaps	Future directions
Diagnosis	Moderate (case-control)	AUC 0.68; sensitivity/specificity 63.6%; independent predictor (OR 1.050)[16]; meta-analysis AUC 0.92[20]	Lack of validation in independent cohorts; optimal cut-off undefined; heterogeneity in assays	Multi-center validation; integration into multi-marker panels; harmonization of assays
Early detection	Limited	Performance varies widely; correlation with stage and metastasis[19,20,56]	Limited data on stage I-II; no screening cohort studies	Evaluation in asymptomatic populations; comparison to FIT and colonoscopy
Prognosis	Moderate (retrospective cohorts)	Correlates with OS and PFS in multiple studies[19,20,31,54-56]; independent of other inflammatory markers[55]; associated with liver metastasis[53,58]	Predominantly retrospective; heterogeneous cut-offs; limited validation in prospective cohorts	Large prospective cohorts with long-term follow-up; integration with ctDNA and CEA; define standardized cut-offs
Predictive (anti-angiogenic)	Preliminary	Baseline IL-8 associated with bevacizumab response in mCRC[58]	Retrospective analyses; heterogeneous populations	Prospective validation in biomarker-directed trials
Predictive (immunotherapy)	Exploratory	IL-8 dynamics correlate with immunotherapy response in melanoma/NSCLC[40]; relevance to CRC uncertain	Limited to melanoma/NSCLC; scarce CRC data, particularly in pMMR/MSS	Evaluation in CRC ICI trials, particularly pMMR/MSS; prospective biomarker-stratified studies
Monitoring	Not established	No longitudinal data; IL-8 lacks tumor specificity[21]; cfDNA shows earlier recurrence detection[65]	Cross-sectional design only; no comparison to ctDNA kinetics	Serial measurement studies; comparison to ctDNA dynamics; assessment of confounding factors
Therapeutic targeting	Preclinical	IL-8/CXCR2 inhibitors in development; KO models show reduced tumor growth[63,64]	No clinical trials in CRC	Phase I/II trials of IL-8/CXCR2-targeted agents; combination with chemotherapy and immunotherapy

IL-8: Interleukin-8; CRC: Colorectal cancer; AUC: Area under the curve; OR: Odds ratio; FIT: Fecal immunochemical test; CEA: Carcinoembryonic antigen; ctDNA: Circulating tumor DNA; cfDNA: Cell-free DNA; OS: Overall survival; PFS: Progression-free survival; mCRC: Metastatic colorectal cancer; NSCLC: Non-small cell lung cancer; pMMR: Proficient mismatch repair; MSS: Microsatellite stable; ICI: Immune checkpoint inhibitor; KO: Knockout; CXCR2: C-X-C motif chemokine receptor 2.