Tumor-associated neutrophils and survival outcomes in colorectal cancer: a systematic review and multilevel meta-analysis

TL;DR

This study finds that high levels of tumor-associated neutrophils in colorectal cancer are linked to better cancer-specific survival, though effects on overall survival depend on factors like tumor stage and detection methods.

Contribution

A multilevel meta-analysis showing TANs as an independent favorable prognostic factor for cancer-specific survival in CRC.

Findings

High TAN infiltration is associated with improved cancer-specific survival in CRC.

Associations with overall and disease-free survival depend on tumor stage and region.

Tumor stage and TAN markers are major sources of heterogeneity in survival outcomes.

Abstract

Tumor-associated neutrophils (TANs) are abundant in the colorectal cancer (CRC) microenvironment, but their prognostic relevance remains controversial. We conducted an updated systematic review and multilevel meta-analysis to evaluate associations between TAN infiltration in primary tumors and survival outcomes in CRC.

PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to January 1, 2026. We included studies of histologically confirmed CRC that quantified TANs in primary tumors and reported hazard ratios (HRs) for cancer-specific survival (CSS), overall survival (OS), or disease-free survival (DFS); recurrence-free survival was combined with DFS. Multilevel random-effects models accounted for correlated effect sizes and generated overall and region-specific estimates from univariate and multivariate analyses. Prespecified subgroup analyses and multilevel meta-regression explored heterogeneity by study region, tumor stage, detection method, and TAN markers.

Twenty-five studies (10,356 patients) were included. High TAN infiltration was consistently associated with improved CSS (univariate HR 0.58, 95% CI 0.48–0.71; multivariate HR 0.66, 95% CI 0.54–0.81) with low heterogeneity across tumor regions. For OS and DFS, pooled estimates suggested an overall protective trend with substantial heterogeneity; subgroup analyses indicated stronger protective associations in Euro–American cohorts and in stage I–III disease. In contrast, multivariate DFS models suggested higher recurrence risk in Euro–American populations and in studies with unclear TAN marker reporting. Meta-regression identified tumor stage and TAN markers as major contributors to heterogeneity in OS and DFS.

High TAN infiltration is a robust, independent favorable factor for cancer-specific survival in CRC. Associations with OS and DFS are context-dependent and appear modified by tumor stage and methodological factors, particularly TAN markers and detection methods, supporting refined prognostic stratification and further study of neutrophil-targeted strategies.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023493604, identifier CRD42023493604.

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