Editor’s Note: The 2026 CSCO Annual Meeting was held in Jinan from September 16 to 19, bringing together scholars from around the world in its international sessions. Prof. Kai-Keen Shiu of the UCL Cancer Institute delivered a special lecture titled “Immuno-resistant CRC treatment” at the conference. Oncology Frontier–UroStream conducted an exclusive interview with him on site, systematically covering the core mechanisms of immunotherapy-resistant colorectal cancer (CRC), breakthrough strategies for microsatellite-stable (MSS) tumors, and practical experience in biomarker testing and patient management. He also shared his assessment of China’s progress in precision therapy and immunotherapy, as well as his expectations for future China–international collaboration, providing valuable reference for CRC treatment in China.Oncology Frontier–UroStream: You shared the topic “Immuno-resistant CRC treatment” at the CSCO international session. Could you briefly introduce the key mechanisms of immunotherapy-resistant colorectal cancer?
Prof. Kai-Keen Shiu: Thank you for the invitation; this is a very good question. We have long recognized that the vast majority of CRC patients have MSS tumors — that is, tumors with proficient mismatch repair (pMMR). Among patients with advanced disease, this proportion exceeds 90%; even among patients at earlier stages, it accounts for 70% to 80%.
Therefore, unlike the “transformative” therapy seen in MSI-H/dMMR CRC — as shown in KEYNOTE-177, CheckMate 8HW, and now the NICHE studies, among many others — where immunotherapy can elicit a very strong immune response that enables the immune system to kill tumors much like it clears viruses or bacteria, this effect does not occur in MSS/pMMR colorectal cancer.
So strictly speaking, this is not entirely “resistance” per se, but rather the underlying tumor biology that makes immunotherapy unlikely to work. The fundamental reason is that these tumors carry a limited number of mutations and can hardly generate so-called neoantigens. Therefore, when PD-1 inhibitors or CTLA-4 inhibitors are used, they indeed cannot elicit the immune response as expected. The mechanisms of resistance are not yet fully understood — we have not even completely figured out how immunotherapy works.
But what makes immunotherapy exciting is that it mobilizes the patient’s own immune system to kill tumors. So we believe that at least about a quarter of patients with MSS/pMMR CRC are sensitive, and the key is to identify this subgroup. For the remaining patients, we need to make changes: either switch to different drugs, or alter the tumor microenvironment in some way — that is, adopt combination strategies, combining other checkpoint inhibitors, therapeutic vaccines, and various forms of chemotherapy or radiotherapy.
Oncology Frontier–UroStream:For colorectal cancer patients who derive limited benefit from immunotherapy or develop resistance, what treatment strategies are currently being explored? What do you consider the key directions for overcoming immunotherapy resistance in the future?
Prof. Kai-Keen Shiu: That’s a good question. Let me answer it in two parts, because my presentation mainly focused on immunotherapy for MSS/pMMR tumors. Briefly, as mentioned in the talk, one direction is to use next-generation immune checkpoint inhibitors to turn “cold tumors” into “hot tumors,” thereby overcoming resistance. We are also combining radiotherapy in CRC, and therapeutic vaccines may be reintroduced in the future.
The other issue you raised — which I touched on only briefly in my presentation but is very important — is that even in MSI-H/dMMR tumors, at least 10%–15% of patients still have primary or acquired resistance after immunotherapy, and it is not easy to figure out the underlying mechanisms.
But we are not without options. There is a class of drugs called Werner helicase (WRN) inhibitors, which, based on the principle of synthetic lethality, allosterically inhibit the WRN helicase activity that MSI-H/dMMR tumor cells are highly dependent on, leading to stalled DNA replication forks and double-strand breaks, thereby selectively inducing apoptosis of tumor cells. At the same time, we are also considering next-generation CTLA-4 inhibitors and combination regimens with other types of drugs.
So I think this is a very attractive field: although immunotherapy has changed the treatment landscape for MSI-H/dMMR patients, patients will eventually develop resistance. Therefore, we need biomarkers to predict the onset of resistance before the situation becomes irreversible; at the same time, biomarkers such as ctDNA may also help guide patients’ next treatment choices.
Oncology Frontier–UroStream:Precisely identifying patients who benefit from immunotherapy and detecting biomarkers that can predict the risk of resistance in advance are expected to improve overall treatment outcomes in CRC. What testing or management experience do you have in clinical practice? Which biomarkers or testing strategies are most likely to change clinical decision-making in the future?
Prof. Kai-Keen Shiu: I believe that, whether we follow the CSCO, ESMO, ASCO, or NCCN guidelines, the most important thing is to get the fundamentals right from the start: test early and obtain as much information as possible from tissue or blood, including ctDNA testing. At a minimum, the basic tests should include MMR testing, MSI testing, KRAS, NRAS, BRAF, HER2, PI3K, and PTEN. These are the least information we need to know; at the very least, they help determine whether a patient should prioritize chemotherapy or immunotherapy in the first-line setting.
We are now accumulating new insights, especially on KRAS. Multiple KRAS inhibitors have been emerging for different subgroups. And the principle I personally practice is: if conditions allow, fully consider the patient’s needs and performance status, and always think one step ahead. That is, even if you have settled on a first-line regimen, plan in advance: once the patient progresses or develops resistance, what is the next step? Surgery, radiotherapy, or enrollment in a clinical trial?
To achieve this, the prerequisite is having real-time biomarker testing results, and ctDNA testing can also be put to use. Another very important thing is to rely on a truly high-level multidisciplinary team (MDT), using the tumor MDT to help patients make the best treatment decisions that can prolong survival.
Finally, I would say that we will eventually have immunotherapy-related biomarkers in the future, but at present they are harder to find. So the real next challenge is: can we find predictive biomarkers for immunotherapy efficacy, especially for patients with MSS/pMMR CRC?
Oncology Frontier–UroStream:As an international expert, how do you assess China’s development in CRC precision therapy and immunotherapy in recent years? What are your expectations for future collaboration with Chinese experts and research teams?
Prof. Kai-Keen Shiu: When I visited CSCO several years ago, I was already impressed by the innovation, vitality, and commitment shown by pharmaceutical companies, researchers, and clinicians. And today, this vitality has been even more fully confirmed. Whether you attend ESMO in person, browse ESMO or CSCO materials, or watch online livestreams, you will see more and more Chinese research and abstracts on the international stage. This shows that peers outside China are also eagerly following the work you are doing.
In my view, about half of the world’s new drugs originate from China, and the same is true for oncology drugs. Therefore, it is essential for us to understand, evaluate, and validate your achievements, and to develop in-depth collaboration on that basis. This is truly exciting.
As demonstrated at this year’s CSCO, Prof. Fabrice André of ESMO delivered a special address, and ASCO also sent representatives. Major international oncology organizations are all eager to join hands with all parties in China — including patients, scientists, clinicians, and oncologists — to bring the drugs you have successfully validated in clinical trials to more patients around the world. This is truly an exciting era. Congratulations — you are doing an excellent job.
