Tailored administration of adjuvant chemotherapy (ACT) enhances treatment efficiency and postoperative well-being in individuals with stage II–III colorectal cancer (CRC). Nonetheless, reliable biomarkers capable of forecasting responses to 5-fluorouracil (5-FU) and oxaliplatin remain insufficient. Three separate cohorts comprising 1676 stage II–III surgical cases were assessed to determine the prognostic value of 12 inflammatory markers. Using multivariable Cox modeling, we generated a novel Chronic Inflammatory Comprehensive Signature (CICS). We compared 3-year recurrence-free survival (RFS) and overall survival (OS) between CICS-based groups (CICS-L vs CICS-H) treated with either 5-FU– or oxaliplatin-based ACT. Two new inflammatory ratios (FPSIIR, FPSIRIR) along with six combined indices (FPSIIS, FPSIRIS, FPSIRS, FASIIS, FASIRS, FASIRIS) consistently predicted outcomes across all cohorts (all plog-rank < 0.05). CICS reached an AUC of 0.690, which increased to 0.724 when integrated with CEA-CA19-9. Individuals categorized as CICS-H showed diminished responsiveness to both drugs, with evident therapeutic benefit mainly in the CICS-L group. For stage II patients within the CICS-L category, similar favorable RFS was found in those receiving 5-FU alone or oxaliplatin-based ACT, compared with non-ACT management (97.73% vs 91.02% vs 91.46%, plog-rank = 0.33). In contrast, stage II CICS-H patients had better survival and fewer recurrences when treated with 5-FU rather than oxaliplatin-based regimens. In stage III cases, both CICS-H and CICS-L subgroups demonstrated clearer benefit from oxaliplatin relative to 5-FU. Optimal ACT choices differed between CICS-L and CICS-H across stages. A CICS-driven approach improved regimen selection (RR = 0.47, 95% CI = 0.35–0.62, p < 0.01) and increased therapeutic performance (HR = 0.70, 95% CI = 0.53–0.92 for RFS; HR = 0.70, 95% CI = 0.47–0.97 for OS in stage III CRC). Higher CICS-defined inflammation corresponds to reduced sensitivity to 5-FU/oxaliplatin. Employing CICS to guide ACT enables precise de-escalation while still maximizing clinical benefit, thereby supporting a biomarker-oriented model for individualized postoperative CRC care.
