Published online Nov 15, 2026. doi: 10.4251/wjgo.124022
Revised: July 27, 2026
Accepted: September 10, 2026
Published online: November 15, 2026
Processing time: 144 Days and 14.4 Hours
Immune checkpoint inhibitors (ICIs) show limited efficacy as monotherapy in microsatellite stable/proficient mismatch repair (MSS/pMMR) metastatic colorectal cancer (mCRC), largely due to an immunosuppressive tumor microenvironment with low T-cell infiltration. Preclinical studies suggest chemotherapy induces immunogenic cell death, while anti-angiogenic agents normalize tumor vasculature, potentially synergizing with ICIs to enhance antitumor immunity. However, real-world evidence for this combination remains insufficient, and whether clinical factors like tumor location or metastasis pattern influence outcomes requires validation. This study evaluated ICI-based combination therapy in MSS/pMMR mCRC using propensity score-based methods.
To evaluate ICI-based combination therapy efficacy and explore prognostic modeling and dynamic inflammatory biomarkers in MSS/pMMR mCRC.
A total of 123 patients with MSS/pMMR mCRC were retrospectively enrolled. ICI-based combination therapy was compared with chemotherapy plus bevacizumab alone. Propensity score matching and inverse probability of treatment weighting were applied to reduce confounding, and E-value analysis assessed unmeasured confounding. The primary endpoint was progression-free survival (PFS). A prognostic nomogram was developed and temporally validated. Associations between post-treatment changes in inflammatory biomarkers and PFS were also evaluated.
After propensity score matching, ICI-based therapy was associated with longer PFS (hazard ratio = 0.486, P = 0.026), with consistent inverse probability of treatment weighting findings. Multivariable regression identified combination therapy as independently favorable and liver metastasis as unfavorable for PFS. Subgroup analyses suggested numerically greater benefits in right-sided and non-liver-metastasis patients, but interaction tests were not significant. A prognostic nomogram showed moderate discrimination temporally (C-index: 0.676-0.695). In exploratory analyses, elevated post-treatment neutrophil-to-lymphocyte ratio and systemic immune-inflammation index were associated with worse PFS in the overall cohort. Grade ≥ 3 adverse event rates were comparable between groups.
ICI-based combination therapy improved PFS with manageable safety in MSS/pMMR mCRC. Nomogram and dynamic neutrophil-to-lymphocyte ratio/systemic immune-inflammation index monitoring may facilitate risk stratification and warrant prospective validation.
Core Tip: Immune checkpoint inhibitors have limited efficacy in microsatellite stable/proficient mismatch repair metastatic colorectal cancer. This real-world study showed that immune checkpoint inhibitor-based combination therapy with chemotherapy and anti-angiogenic agents was associated with improved progression-free survival after propensity score adjustment. Liver metastasis and tumor sidedness showed exploratory prognostic and treatment-related signals, although subgroup findings require further validation. Post-treatment neutrophil‑to‑lymphocyte ratio and systemic immune‑inflammation index may provide additional risk stratification value. These findings offer clinically relevant evidence supporting further prospective evaluation of immune checkpoint inhibitor-based combination strategies in microsatellite stable/proficient mismatch repair metastatic colorectal cancer.