To systematically evaluate the efficacy and safety differences between immune combination regimens and single-agent chemotherapy/single-agent targeted therapy in the third-line treatment of metastatic colorectal cancer (mCRC), providing an evidence-based basis for the selection of later-line strategies.

This systematic review was conducted according to the PRISMA 2020 statement and a predefined PICO framework. PubMed, Embase, Cochrane Library, Web of Science, Scopus, CNKI, Wanfang, VIP and SinoMed were searched from inception to December 31, 2025. Randomized trials, prospective studies and controlled cohort studies comparing immune combination regimens (group T) with single-agent chemotherapy/targeted therapy or stratifiable conventional later-line control regimens (group C) were included. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and adverse events were extracted. RevMan 5.4 was used for Meta-analysis. Dichotomous outcomes were pooled as risk ratios (RR) with 95%CI. Heterogeneity was assessed using Cochran’s Q test and I² statistics, and sensitivity analyses and publication-bias assessments were performed.

The included studies were published between 2021 and 2025, with the combination mode primarily consisting of anti-angiogenic small molecules (regorafenib, fruquintinib, apatinib, etc.) combined with PD-1 inhibitors. ORR (582 cases in Group T and 543 cases in Group C) showed that the combined regimen significantly improved the objective response rate [OR=3.55, 95%CI: 2.38~5.29, P＜0.001]. DCR (504 cases in Group T and 465 cases in Group C) also significantly increased [OR=2.20, 95% CI: 1.49~3.26, P=0.001]. PFS (850 cases in Group T and 1 022 cases in Group C) demonstrated a statistical advantage for the combined regimen [OR=1.35, 95% CI: 1.08~1.68, P=0.008]. OS (836 cases in Group T and 1 008 cases in Group C) also significantly improved [OR=2.08, 95% CI: 1.44~2.99, P=0.001]. In terms of safety (770 cases in Group T and 941 cases in Group C), there was no statistically significant difference in the overall incidence of adverse reactions [OR=1.18, 95% CI: 0.94~1.47, P=0.150]. The heterogeneity for each outcome was low (I²≈0%).

The efficacy of immunotherapy combined regimen in the treatment of mCRC patients as a third-line therapy is superior to that of monotherapy chemotherapy/targeted therapy, significantly improving ORR and DCR, prolonging PFS and OS, and maintaining comparable safety. This provides a reference for clinical later-line treatment.