### Abstract: New Immunotherapy Regimen Breaks Through Treatment Barriers for Advanced Colorectal Cancer **Background:** Colorectal cancer (CRC) is one of the most common and high-incidence malignant tumors in China. The 2020 China Cancer Statistics Report indicates that CRC ranks second in incidence and fifth in mortality among all malignant tumors. For patients with metastatic colorectal cancer (mCRC) who are not eligible for surgical resection, the prognosis is limited after standard chemotherapy and targeted therapy. While immune checkpoint inhibitors (ICIs) have shown promise in treating microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) CRC, the majority (over 90%) of patients with microsatellite stable (MSS) or mismatch repair-proficient (pMMR) CRC do not benefit from single-agent ICI therapy. This has been a significant challenge in the field of CRC treatment, prompting extensive research to find effective solutions. **Research Overview:** On March 4, 2024, the prestigious medical journal *Nature Medicine* published a study titled "Combination of Anti-PD-1, HDAC Inhibitor, and Anti-VEGF for MSS/pMMR Colorectal Cancer: A Randomized Phase II Clinical Trial." The study, led by Professors Xu Ruihua and Wang Feng from the Sun Yat-sen University Cancer Center, reports the detailed findings of the CAPability-01 clinical trial, a nationwide multicenter study. This research aimed to explore a novel triple-drug regimen for MSS/pMMR CRC patients who have failed standard treatments. **Study Design and Participants:** The CAPability-01 trial was a randomized, two-arm, phase II study conducted at four centers in China: the Sun Yat-sen University Cancer Center, the First Affiliated Hospital of Zhejiang University School of Medicine, the First Affiliated Hospital of Guangxi Medical University, and the Cancer Hospital of Harbin Medical University. The study enrolled 48 patients with MSS/pMMR mCRC who had progressed after standard therapy. Patients were randomly assigned to either a triple-drug group (treated with chidamide, sintilimab, and bevacizumab) or a double-drug group (treated with chidamide and sintilimab). **Primary and Secondary Endpoints:** The primary endpoint was the progression-free survival (PFS) rate at 18 weeks. Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and safety. **Key Findings:** - **Overall 18-Week PFS Rate:** The overall 18-week PFS rate was 42.6% for both groups, meeting the study's primary endpoint. - **Median PFS:** The median PFS for the double-drug group was 1.5 months, while for the triple-drug group, it was significantly longer at 7.3 months. - **Objective Response Rate (ORR):** The ORR for the triple-drug group was 44.0%, compared to 13.0% for the double-drug group. - **Disease Control Rate (DCR):** The DCR for the triple-drug group was 72.0%, compared to 39.1% for the double-drug group. - **Duration of Response (DOR):** The median DOR for the triple-drug group was 12.0 months. **Subgroup Analysis:** In patients with liver metastases, the triple-drug regimen also demonstrated superior efficacy: - **18-Week PFS Rate:** 64.0% in the triple-drug group vs. 21.3% in the double-drug group. - **Median PFS:** 7.3 months in the triple-drug group vs. 1.4 months in the double-drug group. - **ORR:** 50.0% in the triple-drug group vs. 8.3% in the double-drug group. - **DCR:** 71.4% in the triple-drug group vs. 8.3% in the double-drug group. **Mechanistic Insights:** RNA sequencing and gene set variation analysis (GSVA) revealed that patients in the triple-drug group who responded to treatment showed increased levels of CD8+ T cells, cytotoxic lymphocytes, and monocytes within the tumor microenvironment, along with decreased levels of B cells, endothelial cells, and fibroblasts. Gene enrichment analysis indicated that multiple immune-related pathways were upregulated in the triple-drug group. These findings suggest that the combination therapy enhances the antitumor immune response from antigen presentation to effector cell activation. **Clinical Implications:** The CAPability-01 study's results are groundbreaking for MSS/pMMR CRC, a subtype that constitutes 95% of all CRC cases. Previous attempts to improve outcomes with ICI combinations and anti-angiogenic therapies, such as the REGOTORI study led by Professors Xu and Wang, achieved only modest results with an ORR of 15.2% and a median PFS of 2.1 months. The novel triple-drug regimen in CAPability-01, however, achieved nearly three times the ORR and five times the PFS benefit compared to prior efforts. **Future Directions:** Building on the success of CAPability-01, a larger phase III trial, CAPability-02, has been initiated to further evaluate the triple-drug regimen as a second-line treatment for advanced CRC. This trial is currently being conducted at 17 centers across China. The innovative approach of combining an HDAC inhibitor, an ICI, and an anti-angiogenic drug may also have broader applications in treating other types of cancer, potentially reshaping treatment paradigms in oncology. **Conclusion:** The CAPability-01 study, led by Professors Xu Ruihua and Wang Feng, has made a significant breakthrough in the treatment of MSS/pMMR advanced colorectal cancer. The triple-drug regimen of chidamide, sintilimab, and bevacizumab demonstrated substantial improvements in PFS, ORR, and DCR, offering new hope for patients who have exhausted standard treatments. This research underscores the importance of translational research from the laboratory to the clinic and highlights the innovative capabilities of Chinese clinical scientists in advancing cancer therapy. **Authors:** Professors Xu Ruihua and Wang Feng from the Sun Yat-sen University Cancer Center are the corresponding authors. The co-first authors are Professor Wang Feng, Deputy Chief Physician Jin Ying, Doctor Wang Min, Chief Physician Luo Huiyan from the Sun Yat-sen University Cancer Center, and Professor Fang Weijia from the First Affiliated Hospital of Zhejiang University School of Medicine. **Link to the Paper:** https://www.nature.com/articles/s41591-024-02813-1