Abstract:Background and Aims Microsatellite-stable (MSS) colorectal cancer (CRC) generally exhibits poor responsiveness to immune checkpoint inhibitors (ICIs), and effective immunotherapy strategies remain lacking. Anti-angiogenic agents such as bevacizumab (BEV) can improve the tumor immune microenvironment and act synergistically with ICIs. This multicenter real-world study compared the efficacy of different immunotherapy-based combination regimens in patients with MSS/MSI-L/pMMR advanced CRC, aiming to identify the optimal treatment strategy.Methods A total of 100 patients with MSS/MSI-L/pMMR advanced CRC who received systemic treatment between November 2019 and February 2025 at four tertiary hospitals in Hunan, China, were retrospectively enrolled. Patients were classified into six treatment groups: chemotherapy alone, chemotherapy + targeted therapy, immunotherapy alone, immunotherapy + chemotherapy, immunotherapy + targeted therapy, and immunotherapy + chemotherapy + targeted therapy. The primary endpoints were overall survival (OS) and progression-free survival (PFS), while secondary endpoints were objective response rate (ORR) and disease control rate (DCR). Additionally, among patients receiving immunotherapy, subgroup analysis was performed according to BEV administration.Results Among all 100 patients, the immunotherapy + chemotherapy + targeted therapy group achieved the highest ORR (32.0%) and DCR (76.0%) and was the only regimen yielding a complete response (CR). Compared with chemotherapy or immunotherapy alone, the triplet regimen significantly improved OS (P<0.05); although PFS improvement did not reach statistical significance, a clear late-stage separation of survival curves was observed. In the immunotherapy subgroup, BEV-containing regimens achieved markedly better outcomes than non-BEV regimens, with DCR of 75.0% vs. 48.8%, median OS of 18.9 vs. 11.5 months, and median PFS of 13.8 vs. 7.2 months (all P<0.001). Cox regression analysis showed that compared with chemotherapy alone, the triplet regimen significantly reduced the risk of death (HR=0.11) and disease progression (HR=0.25) (both P=0.002). Vascular invasion was identified as an adverse prognostic factor for PFS (HR=3.0, P=0.007).Conclusion This multicenter real-world study demonstrated that combining immunotherapy with chemotherapy and targeted therapy significantly improves DCR and survival outcomes in patients with MSS/MSI-L/pMMR advanced CRC, with BEV-containing triplet regimens providing the most pronounced benefit. BEV may enhance immune responsiveness by modulating the tumor microenvironment and promoting effector T-cell infiltration, offering a promising therapeutic direction for "immune-cold" CRC. Prospective randomized studies are warranted to further validate its clinical value and define appropriate patient populations.