From September 16 to 19, 2026, the 29th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO), jointly organized by CSCO and the Beijing Xisike Clinical Oncology Research Foundation, was held in Jinan, Shandong Province, China. The meeting brought together oncology experts from China and around the world to address real-world clinical challenges, share cutting-edge advances, and engage in discussions on novel drug development and optimization of diagnostic and treatment strategies, fostering in-depth academic exchange between the international oncology community.During the conference, Oncology Frontier – Digestive Oncology invited Professor Heinz-Josef Lenz of the USC Norris Comprehensive Cancer Center for an exclusive interview. Drawing on his conference presentation, Professor Lenz discussed immunotherapy for microsatellite instability-high (MSI-H) and microsatellite-stable (MSS) colorectal cancer, systematically examining the latest therapeutic advances, the challenges and limitations encountered in clinical practice, and future directions in precision treatment. The key insights from the interview are presented below.
Q1: We noticed that you shared the latest advances in immunotherapy for colorectal cancer at this conference. Could you please, in the context of your presentation, introduce several of the most groundbreaking innovative therapies or clinical studies? What far-reaching impact will these advances have on current clinical practice?
Oncology Frontier:
Professor Heinz-Josef Lenz:
I think we have made significant progress in treating MSI-H tumors. They are highly sensitive to immune checkpoint inhibitors, including not only PD-1 or PD-L1 inhibitors. Recent data have shown that the combination of CTLA-4 and PD-1 inhibitors is superior and more effective than PD-1 inhibitor monotherapy. I think we have learned that CTLA-4 plays a significant role in immunotherapy for both MSI-H and MSS disease.
One particularly important lesson is that the sequence of treatment matters. For patients with MSI-H tumors, immunotherapy should be initiated early rather than deferred to later lines of treatment. It is therefore absolutely critical to test every patient newly diagnosed with metastatic colorectal cancer for MSI status, KRAS mutations, BRAF mutations, and HER2 amplification. This molecular characterization is essential to ensure that patients receive the most effective treatment. Delaying appropriate treatment until later lines can mean losing an opportunity to achieve greater efficacy.
Another breakthrough involves MSS tumors. Fc-engineered CTLA-4 antibodies and masked CTLA-4 antibodies have demonstrated efficacy in MSS tumors, which have traditionally been considered resistant to immune checkpoint inhibitors. Combining these engineered CTLA-4 antibodies with PD-1 inhibitors has shown substantial efficacy in patients with extrahepatic disease. However, tumors with liver metastases do not respond as well, likely because of the immunosuppressive microenvironment in the liver. These studies are ongoing and have paved the way for the further development of immunotherapy for MSS disease.
Another major advance is in the neoadjuvant setting. Patients with MSI-H rectal cancer benefit dramatically from immune checkpoint inhibitors. Not only can they achieve very high rates of complete clinical response, reaching up to 100%, but they may also avoid surgery that would require a stoma, as well as chemotherapy and radiotherapy. This means that patients can avoid many of the complications associated with these locoregional treatments.
Q2: Despite the progress made, precision treatment for colorectal cancer still faces challenges. What do you think are the primary bottlenecks limiting the improvement of immunotherapy efficacy in MSI and MSS patients? In your view, what emerging targets or combination strategies hold clinical translation potential to help overcome these bottlenecks?
Oncology Frontier:
Professor Heinz-Josef Lenz:
I think one of the biggest bottlenecks is whether patients are actually tested. Another challenge is the reliability of the test results. Immunohistochemistry and next-generation sequencing can have different sensitivities. Large randomized trials have shown that discordance between test results can reach as high as 20%. It is therefore absolutely critical to have a reliable pathology laboratory and confidence in the immunohistochemistry results. In accordance with the European Society for Medical Oncology (ESMO) guidelines, and in my own practice, I use both next-generation sequencing and immunohistochemistry to ensure that I can rely on the MSI testing results.
Another interesting finding is not necessarily a bottleneck, but rather an ongoing challenge: with either monotherapy or combination treatment, we see complete clinical response rates of approximately 30%–35% in patients with metastatic disease. We do not yet know how to identify these patients in advance. If we could, we might not need to use combination treatment in every patient, thereby reducing toxicity by administering monotherapy to those who would benefit from it.
We have made considerable progress in using CTLA-4 antibodies in clinical practice to manage and prevent toxicities. Importantly, only four cycles of low-dose CTLA-4 antibody treatment are needed to maintain high efficacy.
For MSS disease, no immunotherapeutic agents have yet been approved. However, ongoing studies combining engineered CTLA-4 antibodies with PD-1 inhibitors have shown very promising results, with response rates reaching approximately 30%–35%. I believe there is a good chance that immunotherapies will be approved for metastatic and potentially locally advanced MSS colorectal cancer. Similar experiences with CTLA-4 antibodies in MSS disease have also been reported in China.
There are many opportunities to further improve the efficacy of these combinations. Studies from China have shown that adding COX-2 inhibitors may further enhance treatment efficacy. I believe a range of novel combination strategies has the potential to improve immunotherapy outcomes in MSS tumors.
Q3: Looking ahead, could you share which directions your team is currently exploring or will prioritize in the future? For example, biomarker stratification, novel immunotherapy, or special population expansion, to further advance the precision treatment of colorectal cancer?
Oncology Frontier:
Professor Heinz-Josef Lenz:
There are many ongoing clinical trials exploring the use of immune checkpoint inhibitors in the form of bispecific antibodies in the first-line setting, in combination with chemotherapy, with or without bevacizumab. Positive trial results with bispecific antibodies could change the treatment paradigm for patients with MSS disease receiving first-line therapy. Early data suggest that response rates may reach as high as 70% in first-line treatment of MSS metastatic colorectal cancer (mCRC) with bispecific antibodies.
Considerable effort is also being devoted to identifying which patients with MSS disease are most likely to benefit from first-line immunotherapy. I am very optimistic that we will see more effective and less toxic immunotherapies for our patients.
For example, my research group is working on novel compounds to improve the efficacy of immune checkpoint inhibitors. I believe the future lies in leveraging the molecular makeup of tumors and cytokine networks within the tumor microenvironment to identify better therapeutic targets for patients with MSS colorectal cancer.
Professor Heinz-Josef Lenz
