To the knowledge, this is the first study to analyze postoperative/preoperative inflammatory factor ratios in relation to survival outcomes among patients who underwent radical resection of CRC. Analysis of 12 inflammatory factors revealed that a high postoperative-to-preoperative IL–1β ratio was significantly associated with poorer survival. Inflammation plays a significant role in shaping the development of CRC. Consequently, the expression of inflammatory factors in CRC has attracted considerable attention from researchers. Previous studies examining single time points have revealed that inflammatory factors such as IL–612,13, IL–814, and IL–1011are associated with tumor prognosis. However, Amicarella et al.15 reported no correlation between IL–17 levels and tumor prognosis in their study involving more than 1,000 CRC patients. Although single–time–point testing is simple and practical, multiple factors may influence the expression of inflammatory factors. To avoid confounding effects on predictive efficacy, this retrospective study enrolled 153 patients who underwent radical resection for CRC and focused on postoperative/preoperative inflammatory factor ratios to explore their predictive value.
The findings revealed significantly elevated levels of inflammatory factors after surgery, including IL–6 and IL–10, whereas the levels of IFN–γ, IL–12p70, IL–17, and TNF–α were decreased. Perioperative stable inflammatory factors included IL–1β, IL–2, and IL–8. The postoperative elevation of these factors may be attributed to their heightened sensitivity and intensity in response to surgical procedures, anesthesia, and stress, thereby explaining their widespread use in systemic inflammatory monitoring. However, this study revealed no correlation between these elevated factors and tumor prognosis. IL–1β levels remained relatively stable during the perioperative period. Both univariate and multivariate Cox regression analyses suggested that the postoperative-to-preoperative IL‑1β ratio may be an independent prognostic factor for survival, although this finding should be interpreted with caution, given the limited number of events. Survival analysis further revealed that higher IL–1β ratios were associated with poorer outcomes. These findings suggest the significant potential of the postoperative/preoperative IL–1β ratio for predicting the prognosis of CRC patients.
As a core regulatory factor of inflammatory responses, IL–1β plays a pivotal role in CRC development through multiple pathological processes, including tumor remodeling, immune evasion, angiogenesis, metastasis, and chemotherapy resistance16,17,18,19. A previous study conducted by Dan Nicolae Florescu et al. revealed that compared with healthy individuals, patients with CRC exhibit significantly higher serum IL–1β levels20, thereby indicating its role in CRC diagnosis and prognosis prediction. Marko Vukovic et al.21 reported via immunohistochemical analysis that IL–1β protein expression demonstrates significant prognostic value in bladder cancer tissues. Moreover, Gurcan Tunali et al. demonstrated that IL–1β maintains self–reinforcing mechanisms via the NF–κB and STAT3 signaling pathways, thus promoting the development of an inflammatory environment in triple–negative breast cancer and advancing tumor progression22. This study further suggests that an elevated postoperative-to-preoperative peripheral blood IL‑1β ratio may be associated with CRC cancer‑specific survival, but this association requires validation in larger cohorts. Although this indicator may be influenced by perioperative inflammatory status and other nontumor confounders, the results still suggest the potential of IL‑1β as a prognostic marker, but this should be confirmed in appropriately powered studies. Additionally, the human monoclonal antibody known as canakinumab, which targets IL–1β, has demonstrated antitumor efficacy in clinical trials. For example, the CANTOS trial revealed that this antibody could significantly reduce the incidence of lung cancer23; additionally, IL–1β blockade could significantly reduce the tumor load in the lungs and could also be used as an alternative therapy to existing K–ras–mutant lung adenocarcinoma treatment24, which also provides a new idea for IL–1β inhibition–based CRC treatment strategies.
Notably, Huihui Xiang et al.25demonstrated that IFN–α promotes CRC progression by upregulating NK2R gene expression, which is correlated with poor patient outcomes. However, the univariate Cox regression analysis revealed that elevated postoperative IFN–α levels remained significantly associated with survival, suggesting that this cytokine may contribute to CRC development. However, after adjusting for clinical variables in the multivariate Cox regression analysis, this correlation lost statistical significance. Recent studies have indicated that IFN–α is a potential immunotherapy adjuvant; specifically, it induces PD–1 expression in melanoma cells26 and enhances the immune response27. Moreover, the blockage of IFN–α eliminates the efficacy of anti–PD–1 treatment28. The actual functional state of the IFN–α signaling pathway likely outweighs changes in relative concentration, thereby indicating that isolated IFN–α measurements are insufficient for reliable assessment of CRC prognosis. Therefore, further investigations are needed to elucidate the specific mechanisms of IFN–α in CRC and its potential value as a prognostic biomarker.
However, there were several limitations in this study. Critically, the total number of deaths was only 21, and the multivariate model included six covariates, yielding an events–per–variable (EPV) ratio of approximately 3.5, which is well below the generally recommended threshold of 10. Furthermore, the cutoff value for dichotomizing the IL–1β ratio was derived from the same dataset without external validation, which may lead to overoptimistic estimates of prognostic performance and a substantial risk of overfitting. Moreover, although this research used CSS as the endpoint to isolate cancer‑specific mortality, CSS is not the ideal endpoint for this predominantly early‑stage cohort (69.3% stage I–II) because it excludes non‑cancer deaths and thus limits comparability with standard cancer‑specific survival analyses; DFS/RFS would have been statistically preferable, but recurrence data were not captured in the retrospective registry, preventing such an analysis. The post–hoc stage I–III subgroup analysis (n = 141, 16 events) showed a directionally consistent but non–significant HR of 1.04 (95% CI 0.99–1.10, p = 0.11), which reinforces the limited power of the current dataset. This limited statistical power, together with the small number of events in the high–risk subgroup (n = 5), implies that the findings should be interpreted as exploratory and hypothesis–generating rather than definitive, and require validation in larger independent cohorts.
Additionally, several important determinants of postoperative inflammation and long‑term survival—including adjuvant chemotherapy, surgical approach, MSI status, degree of surgical trauma, anesthesia methods, and antibiotic usage—were not recorded or adjusted for in this retrospective analysis. Because these factors may influence both the IL‑1β ratio and patient outcomes, this research cannot exclude substantial residual confounding, and the observed association cannot be confidently attributed to the IL‑1β ratio itself. First, neither preoperative nor postoperative blood samples were collected at fixed, standardized time points relative to the surgical procedure, and the actual time intervals were not consistently recorded in the retrospective dataset. Because perioperative cytokine levels are highly time‑dependent and the ratio is the primary exposure, this lack of standardization directly compromises the validity and comparability of the IL‑1β ratio across patients; no statistical adjustment can adequately correct for this intrinsic measurement error, and this variability may have substantially affected the prognostic estimate. Given the limited sample size and incomplete time‑interval records, this research was unable to conduct a reliable sensitivity analysis of time heterogeneity, which it acknowledges as a notable limitation. Future prospective studies with predefined postoperative sampling windows are warranted to confirm the reproducibility and clinical utility of the findings. Second, key influencing factors, such as the degree of surgical trauma29, anesthesia methods30, and antibiotic usage31,32, were not stratified in the analysis, thereby limiting a comprehensive assessment of their relationship with prognosis. Finally, the single–centre, retrospective design and relatively small sample size may introduce selection bias, thus affecting the generalizability of the study results. Future large–scale, multicentre prospective studies are warranted to validate the findings, further elucidate the prognostic significance of these inflammatory biomarkers, and enhance the robustness and clinical applicability of the conclusions.
These findings suggest a potential exploratory association between the postoperative–to–preoperative IL‑1β ratio and survival in radically resected CRC patients. However, due to the single-center retrospective design, the absence of adjustment for key perioperative confounders (including surgical trauma, anesthesia, antibiotics, adjuvant therapy, and MSI status), and the lack of recurrence data (which precluded a DFS/RFS analysis), this association cannot be confidently attributed to the IL‑1β ratio itself. Prospective multicentre studies with comprehensive covariate collection and standardized sampling protocols are essential to validate these preliminary observations.