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Mismatch repair-deficient (dMMR) colon cancer, also known as microsatellite instability-high (MSI-H), is a biologically distinct form of colorectal cancer caused by mutations in some of the genes that are involved in correcting mistakes made when DNA is copied in a cell. This type of colon cancer is highly responsive to treatment with immunotherapy, which has reshaped how clinicians’ approach care, leading to major advances across both early-stage and metastatic disease.
Here, we take a closer look at what makes dMMR colon cancer different, why these tumors respond so well to therapies that activate the patient’s own immune system, known as immunotherapy, and how recent research is changing how we approach patients with these tumors. From new first-line treatments for metastatic disease to promising approaches before surgery, these advances are helping many patients with colon cancer live longer and feel healthier, often with fewer side effects than older chemotherapy-only strategies. Understanding the science behind this dMMR colon cancer subtype is helping doctors match the right treatment to the right patient at the right time.
When cells divide, they must copy DNA accurately. The mismatch repair system acts as a molecular proofreader, correcting small errors that occur during cell replication. If this system fails, mutations accumulate throughout the genome. These mutations are then transcripted to proteins that have mutations or alterations. When tumors develop under these conditions, these abnormal proteins, known as neoantigens, are readily recognized by the immune system as foreign. This heightened immune visibility explains why dMMR tumors often show a heavy immune cell infiltration and why they respond so well to a type of immunotherapy known as immune checkpoint inhibitors.
Mismatch repair deficiency can occur spontaneously in the body or due to other genetic conditions, such as Lynch syndrome. Lynch syndrome is an inherited condition that is passed down in families and results in mutations in these mismatch repair genes, resulting in a faulty proofreading system. Lynch syndrome affects roughly one in 280 Americans and having a mutation in one of these repair genes increases the overall risk of developing cancer and at a younger age. People with Lynch syndrome are especially at risk for developing colorectal and endometrial cancers.
Research has shown that approximately 12–15 percent of all colorectal cancers are mismatch repair deficient. Whether the deficiency arises from Lynch syndrome or sporadic causes, immunotherapy responses are similarly strong because the underlying feature of the high mutation burden remains the key driver for these cancers.
The prevalence of dMMR varies by stage. It is more common in early-stage colon cancer and less frequent in metastatic disease, suggesting that tumors capable of spreading may have developed mechanisms to evade immune control.
In stage II and some stage III colon cancers, dMMR status has historically been associated with a better prognosis. These grow more slowly and are recognized by the immune system more effectively. Patients with stage II dMMR colon cancer generally have lower rates of recurrence and improved overall survival compared with stage II colon cancer without dMMR.
That advantage appears to diminish with extensive lymph node involvement and is not seen once the disease becomes metastatic. In metastatic colon cancer, dMMR tumors behave more aggressively. Historically, outcomes for this subset of patients have been similar to, or slightly worse than, mismatch repair–proficient tumors when treated with chemotherapy alone. This resistance to standard cytotoxic regimens has likely contributed to poorer historical outcomes for patients with metastatic mismatch repair deficient colon cancer. Advances in immunotherapy and its incorporation into treatment regimens is changing that.
While initial surgical management is similar for all colon cancers, dMMR tumors have historically not responded as well to chemotherapy, such as FOLFOX or FOLFIRI, compared with other types of colon cancer. This limited the long-term cancer control options for these tumors until the introduction of immune checkpoint inhibitors. Checkpoint inhibitors are a form of immunotherapy that work by helping to lift the brakes off the immune cells (T cells) that are responsible for fighting cancer, allowing them to better recognize the cancer cells in the body.
The most dramatic treatment advance with immune checkpoint inhibitors has occurred in metastatic dMMR colorectal cancer. Multiple large clinical trials demonstrated that PD-1 inhibitors such as pembrolizumab or nivolumab produce higher response rates and more durable disease control than standard chemotherapy. Patients receiving immunotherapy as their first treatment often experience fewer symptoms, delayed disease progression, and in many cases, an improvement in overall quality of life. These clinical trial results have established immunotherapy as the preferred first-line treatment for metastatic dMMR disease, largely replacing chemotherapy for most patients with this subtype of colon cancer.
Combination immunotherapy has further improved outcomes for some patients. Regimens pairing PD-1 inhibitors with CTLA-4 inhibitors, such as nivolumab plus ipilimumab, have shown superior progression-free survival compared with single-agent immunotherapy or chemotherapy. This approach aims to activate the immune system from multiple angles to generate a more powerful response.
While dual therapy can increase immune-related side effects, such as skin, liver, or gastrointestinal tract inflammation, most are manageable with careful monitoring. Because of this, immunotherapy treatment selection is often individualized, with combination therapy favored for younger, fitter patients or those with bulky disease, and single-agent therapy chosen for older or more frail individuals.
As ongoing research studies help to further refine these strategies, immunotherapy continues to reshape the outlook for patients with metastatic dMMR colorectal cancer. What was once a very difficult to treat form of colon cancer now has more treatment options available.
The success of immunotherapy for metastatic dMMR colon cancer has led to research evaluating these treatments in earlier stages of the disease. For years, stage III colon cancer was treated with six months of adjuvant chemotherapy following surgery, which was determined to not be as effective in dMMR tumors. “Building on the advances of using immunotherapy to treat stage four dMMR colon cancer, investigators contemplated the use of immunotherapy earlier on, in patients with stage III dMMR colon cancer,” explains Dr. Shah.
A recent study showed that adding immunotherapy to chemotherapy for stage III dMMR colorectal tumors significantly reduces risk of recurrence, leading to significant updates in treatment guidelines and integration of immune-based approaches earlier in the disease course. These findings have changed the way physicians approach caring for patients with stage III dMMR colon cancer, and these research results have opened the door to using immunotherapy in those with high-risk stage II colon cancer as well.
The role of neoadjuvant immunotherapy, giving the immunotherapy treatment before surgery, is another promising strategy. Treating earlier-stage dMMR tumors before surgery has the advantage of leveraging the intact tumor tissue to try to help stimulate a stronger immune response. Early trials have reported remarkably high rates of tumor regression after just a few doses of immune checkpoint inhibitors, with many patients achieving complete pathologic response. These results raise the possibility that some individuals may eventually require less extensive surgery or shorter courses of postoperative therapy. There may even be potential for some patients to avoid surgery entirely.
Despite the success and promise, not all dMMR tumors respond to immunotherapy, and some patients eventually develop treatment resistance. Research suggests that this “immune escape” can occur through disruptions in antigen presentation, alterations in T-cell receptor signaling and changes in interferon pathways.
Because dMMR tumors share certain recurrent mutations, investigators are exploring vaccine-based approaches for early-stage disease and those at increased risk for developing these cancers due to Lynch syndrome. This vaccine approach may help stimulate the immune system to recognize and kill the cancer early, as well as prevent cancers from forming in the first place. These strategies aim to balance potential benefit with the risk of immune-related side effects.
Since Lynch syndrome increases a person’s risk of multiple cancers over a lifetime, immunotherapy is now being explored not just as a treatment strategy, but also as a potential preventive tool in high‑risk individuals. For families affected by Lynch syndrome, genetic counseling, coordinated surveillance, and emerging prevention strategies form a comprehensive approach that supports both patients and at‑risk relatives.
Dr. Shah highlights that “the future of dMMR colon cancer care is moving towards more precise and less toxic treatment, which is a real benefit that patients truly appreciate.” Researchers are studying novel drug combinations, targeted therapies such as synthetic lethal approaches and cellular therapies. Circulating tumor DNA and immune monitoring may help determine which patients can safely stop treatment and which need longer therapy to prevent disease relapse.
What is clear is that understanding the biology of mismatch repair deficiency has transformed care. Immunotherapy has shifted the paradigm from conventional chemotherapy to immunotherapy-based strategies that offer longer survival and, in some cases, the potential for cure. As research continues, treatment is expected to become even more personalized, aiming to maximize effectiveness while minimizing the burden of therapy.
To hear a more in-depth discussion about this topic, tune in to the CancerCast podcast where host Dr. Manish Shah speaks with two experts to discuss mismatch repair deficient colon cancer and how this subset of colon cancer is managed and treated differently. Listen on Apple Podcasts, Spotify, YouTube, or the Weill Cornell Medicine website.
