The Immunotherapy Landscape in Colorectal Cancer: Where We Stand and Where We're Headed

The Immunotherapy Landscape in Colorectal Cancer: Where We Stand and Where We're Headed

Immunotherapy has transformed treatment for MSI-high colorectal cancer while new strategies are beginning to unlock progress in microsatellite stable disease. In this expert commentary, Ibrahim Halil Sahin, MD, reviews the latest advances in checkpoint inhibitors, TKI–IO combinations, biomarker-driven therapy, and emerging opportunities in early-stage colorectal cancer.

Introduction: A Tale of Two Colorectal Cancers

Colorectal cancer (CRC) is not a single disease, and nowhere is that more apparent than in immunotherapy. The treatment paradigm of microsatellite instability–high (MSI-H) and mismatch repair–deficient (dMMR) subset—roughly 4–5% of metastatic CRC—has been transformed by immune checkpoint blockade. The microsatellite stable (MSS) subset, which represents the overwhelming majority of patients, has been frustratingly resistant. The past two years have brought meaningful progress on both fronts: practice-changing trials in MSI-H disease (KEYNOTE-177, CheckMate-8HW, NICHE), the emergence of new combinations in MSS disease, and the maturation of biomarkers such as BRAF V600E and the presence or absence of liver metastases as drivers of treatment response.

Understanding where immunotherapy works—and where it does not—has become a defining question in modern GI oncology. This article walks through four practical segments: advanced MSI-H disease, localized MSI-H disease, advanced MSS disease, and early-stage MSS disease, where I believe some of the most interesting signals are now emerging.

Expert Analysis: From MSI-H Triumph to MSS Progress

Advanced MSI-H CRC: Pembrolizumab vs. Nivo–Ipi

KEYNOTE-177 established pembrolizumab monotherapy as a frontline standard in MSI-H/dMMR metastatic CRC, with a 16-month progression-free survival (PFS) benefit over chemotherapy. CheckMate-8HW then compared nivolumab plus ipilimumab against nivolumab monotherapy and showed curve separation favoring the doublet. The remaining question is which patients truly need the doublet, given that combination immunotherapy was associated with treatment-related deaths from myocarditis and pneumonitis.

Subgroup signals are informative. Patients with BRAF V600E mutations and those with PD-L1 expression appeared to derive greater benefit from the doublet. Notably, patients without liver metastases also did better with combination therapy—a counterintuitive finding given that the liver microenvironment is often considered immunologically challenging. Our own work, published in 2021, identified BRAF as a biomarker of monotherapy response in MSI-H CRC, and this was subsequently confirmed in a 2024 European Journal of Cancer publication. Liver metastases were prognostic in our analysis but not consistently predictive across studies.

Choosing Monotherapy or Doublet: A Patient-Specific Decision

In practice, I individualize. For high-volume, multi-organ disease where there is no time to wait and see, or for BRAF V600E–mutated tumors—which can behave aggressively and may even involve unusual sites such as brain metastases—the doublet makes sense. For low-volume disease (one or two liver lesions, an asymptomatic patient), monotherapy is reasonable as a starting point, with the option to escalate later. The cost side of the equation—immune-related toxicity, including rare but real treatment-related mortality—must be weighed honestly.

Localized MSI-H CRC: Neoadjuvant vs. Adjuvant

The ATOMIC trial (presented at the 2025 plenary) tested chemotherapy plus atezolizumab versus chemotherapy alone in stage III dMMR colon cancer, with a benefit driven by adding immunotherapy to a chemo backbone over a one-year treatment course. By contrast, the NICHE program demonstrated that just two doses of nivolumab and a single dose of ipilimumab in the neoadjuvant setting produced dramatic pathologic responses and 100% disease-free survival in a single-arm study—an extraordinary signal, even acknowledging the limits of cross-trial comparison.

Knowing what we now know, I find it hard to argue for a year of adjuvant immunotherapy in patients who have not yet had surgery. For the patient already post-resection, the ATOMIC regimen remains the evidence-based approach. For the patient walking into clinic with measurable, resectable disease, the NICHE regimen—short, high-impact, organ-sparing where appropriate—is increasingly my preference, with the caveat that it remains based on single-arm data. The question of organ preservation for colon cancer (analogous to the rectal cancer experience) is still open; surveillance remains harder for colon cancer in general particularly for right-sided disease.

MSS CRC: TKI–IO Combinations Take a Step Forward

MSS CRC has been a graveyard for immunotherapy trials. The original REGONIVO study from Asia generated enthusiasm with a 7.8-month median PFS in third-line MSS CRC, but a Moffitt-led replication in U.S. patients—where liver metastases predominate—showed only a 10% objective response rate and a 4.3-month median PFS. The lesson: liver metastases blunt response, and patient selection matters enormously.

STELLAR-303 (zanzalintinib plus atezolizumab) was ultimately positive, with a modest but real overall survival benefit. The signal opens the door, even if toxicity—possibly tied to higher zanzalintinib dosing—deserves attention. Many other TKI–IO combinations have failed, suggesting that not all TKIs (or all anti–PD-1s) are interchangeable, and that biology matters more than we initially appreciated.

Fc-Enhanced Anti–CTLA-4 and Novel Agents

Fc-enhanced anti–CTLA-4 antibodies aim to deplete intratumoral regulatory T cells. Botensilimab combined with anti–PD-1 has shown activity, primarily in patients without active liver metastases. Higher anti–CTLA-4 doses produced more colitis without clearly better efficacy, leading developers to select lower-dose regimens for randomized study. Beyond this, novel bispecifics targeting PD-1/TGF-β receptor 2 or PD-1/VEGF pathways are entering trials, with intriguing single-agent activity even in patients with liver metastases—a notable signal given the historical TGF-β pathway role in immune exclusion.

Early-Stage MSS Disease: An Underappreciated Opportunity

Perhaps the most provocative data come from neoadjuvant studies in early-stage MSS colon cancer. NICHE included MSS patients and observed complete pathologic responses in a small subset after just two doses of nivolumab plus a single dose of ipilimumab. Similar signals have emerged with Fc-enhanced agents like botensilimab. Whether the activity reflects FC enhancement specifically or something more fundamental about CTLA-4 blockade in early-stage disease is an open question. Either way, the tumor microenvironment in early-stage MSS disease appears to be more immunologically exploitable than its metastatic counterpart.

Clinical Implications and Practice Takeaways

• In metastatic MSI-H/dMMR CRC, frontline immunotherapy—not chemoimmunotherapy—is standard. Choose monotherapy or a nivo–ipi doublet based on disease burden, BRAF V600E status, and patient fitness.
• BRAF V600E mutation should prompt strong consideration of doublet immunotherapy in MSI-H disease; these tumors can behave aggressively.
• In localized MSI-H colon cancer, short-course neoadjuvant immunotherapy (NICHE-style) is increasingly attractive over a year of adjuvant therapy, though randomized confirmation is awaited.
• In MSS metastatic CRC, STELLAR-303 introduces a new TKI–IO option; expect refinement of patient selection and dosing.
• The presence or absence of liver metastases is now a meaningful clinical variable in selecting MSS CRC patients for immunotherapy combinations.
• Early-stage MSS colon cancer may be more immunotherapy-responsive than the metastatic setting—a hypothesis worth pursuing in clinical trials.
• Industry investment in MSS CRC drug development remains an unmet need; advocate for trial enrollment when possible.

Patient Perspective: What This Means for You

Colorectal cancer comes in two main biological flavors. About one in twenty patients with metastatic disease has a type called MSI-high, which often responds remarkably well to immunotherapy—drugs that activate your immune system to fight the cancer. For patients with this type, immunotherapy is now usually the first treatment, sometimes given as one drug and sometimes as two. The two-drug combination can be more powerful but has more side effects, including rare serious ones. Your doctor will weigh how much disease you have and your overall health when making that choice. For the more common MSS type, immunotherapy has historically not worked well, but newer combinations are starting to help selected patients—particularly those without cancer in the liver. The field is moving quickly, and clinical trials remain an important option to discuss.

Key Takeaways

• Frontline immunotherapy alone (not chemoimmunotherapy) is standard in metastatic MSI-H/dMMR CRC.
• BRAF V600E status and liver metastasis status help guide monotherapy vs. doublet decisions.
• Short-course neoadjuvant immunotherapy (NICHE) is increasingly preferred over adjuvant therapy in localized MSI-H colon cancer.
• STELLAR-303 establishes a TKI–IO foothold in MSS CRC; novel bispecifics and Fc-enhanced agents are next.
• Early-stage MSS colon cancer may harbor an underappreciated immunotherapy opportunity worth prospective study.

References and Further Reading

1. André T, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer (KEYNOTE-177). N Engl J Med.
2. Andre T, et al. Nivolumab plus ipilimumab in MSI-H/dMMR metastatic CRC (CheckMate-8HW).
3. Chalabi M, et al. Neoadjuvant immunotherapy in localized dMMR colon cancer (NICHE).
4. Sahin IH, et al. BRAF mutation as a biomarker for response to immune checkpoint inhibitors in MSI-H CRC. 2021 publication and 2024 EJC confirmation.
5. ATOMIC trial: chemotherapy plus atezolizumab in stage III dMMR colon cancer. 2025 plenary.
6. STELLAR-303 (zanzalintinib + alizumab) in refractory MSS CRC.
7. Binaytara: Detroit 2026 Conference Proceedings, binaytara.org.

About the Author

Ibrahim Halil Sahin, MD, is a medical oncologist specializing in gastrointestinal oncology. He is extensively involved in clinical trial development for colorectal cancer and nationally recognized expert in colorectal cancer. Dr. Sahin’s clinical and research interests focus on colorectal designing clinical trials with immunotherapy and targeted therapy for patients with advanced stage colorectal cancer. He is an active member of NCI Colon Task Force and Alliance Gastrointestinal Cancer and Colorectal Cancer Committees. He also currently serves as co-chair of HCRN Gastrointestinal Clinical Trial Working Group.