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Mismatch-repair deficient bowel cancer has lost its DNA spell-checker, so it carries thousands of mutations that the immune system can recognise. Immunotherapy alone controls most metastatic cases for years and makes most localised tumours disappear before surgery, sometimes so completely that no surgery is needed.
Mismatch-repair deficiency arises when MLH1, MSH2, MSH6 or PMS2 is lost, either by sporadic MLH1 promoter methylation (typically right-sided, in older women, often with BRAF V600E) or by a germline mutation in Lynch syndrome, which is why every colorectal cancer is now tested by immunohistochemistry or microsatellite analysis at diagnosis. The tumours accumulate tens of thousands of frameshift mutations, produce abundant neoantigens and are infiltrated by T cells held in check by PD-1; they have a better prognosis when localised and do not benefit from fluorouracil alone as adjuvant therapy.
In metastatic disease KEYNOTE-177 (2020) showed that pembrolizumab alone doubled progression-free survival against chemotherapy (16.5 versus 8.2 months), with 54.8 percent of patients alive at five years and a median survival of 77.5 months; CheckMate 8HW (2024) showed that nivolumab plus ipilimumab cut progression by 79 percent against chemotherapy (median progression-free survival 54.1 versus 5.9 months) and beat nivolumab alone, and the combination was approved first line in April 2025. About a third of patients still progress early, often because of pMMR misclassification, JAK1 or B2M loss or immune-excluded biology.
In localised disease four weeks of neoadjuvant nivolumab and ipilimumab produced pathological complete response in 68 percent of colon cancers in NICHE-2 with no recurrence at three years; the ATOMIC phase 3 trial (2025) showed that adding atezolizumab to adjuvant FOLFOX improves disease-free survival in stage III disease; and in rectal cancer six months of dostarlimab produced a clinical complete response in every patient treated, allowing surgery and radiotherapy to be omitted. For Lynch carriers, colonoscopy every one to two years and daily aspirin (CAPP2) prevent cancers, and frameshift-neoantigen vaccines are in trials.
About 15 percent of localised and 5 percent of metastatic colorectal cancers have lost DNA mismatch repair, most often through methylation of the MLH1 gene in right-sided tumours of older women and, in about a fifth, through inherited Lynch syndrome.
Right-sided tumours behave differently from left-sided and rectal ones; the colon drains along its mesenteric vessels, the rectum into the mesorectum and pelvic side wall.
Same organ: Colon cancer (adenocarcinoma of the colon), Micropapillary adenocarcinoma of the colon and rectum, Adenoma-like adenocarcinoma of the colon and rectum, Lynch syndrome-associated colorectal cancer, Familial adenomatous polyposis-associated colorectal cancer, Mucinous adenocarcinoma of the colon and rectum, Signet ring cell carcinoma of the colon and rectum, Medullary carcinoma of the colon, Serrated adenocarcinoma of the colon and rectum, Peritoneal mesothelioma, Colorectal cancer, Rectal cancer, BRAF V600E-mutant colorectal cancer, HER2-amplified colorectal cancer, KRAS G12C-mutant colorectal cancer, Early-onset colorectal cancer (under 50), Anal cancer (squamous cell carcinoma), Appendiceal cancer and pseudomyxoma peritonei, Small intestine cancer (small bowel adenocarcinoma), Small intestinal neuroendocrine tumours, Anal high-grade squamous intraepithelial lesions (precursor), Localised anal squamous cell carcinoma (stage I to III), Metastatic and recurrent anal squamous cell carcinoma, Low-grade appendiceal mucinous neoplasm and pseudomyxoma peritonei, Appendiceal adenocarcinoma (mucinous and non-mucinous, including signet ring cell), Goblet cell adenocarcinoma of the appendix, Localised small bowel adenocarcinoma (stage I to III, resected), Advanced and metastatic small bowel adenocarcinoma
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
Pembrolizumab alone (KEYNOTE-177) or nivolumab plus ipilimumab (CheckMate 8HW); chemotherapy only if immunotherapy is contraindicated.
Neoadjuvant nivolumab plus ipilimumab for locally advanced tumours (NICHE-2) where available; surgery; adjuvant FOLFOX plus atezolizumab for stage III (ATOMIC); no fluoropyrimidine alone.
Six months of dostarlimab or another PD-1 antibody with non-operative management for complete responders (AZUR-1).
Colonoscopy every one to two years from age 25 (earlier for MLH1 and MSH2), daily aspirin (CAPP2), cascade germline testing of relatives, hysterectomy and oophorectomy after childbearing for women.
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Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
Immunotherapy can attack hormone-producing glands: most often the thyroid (usually ending in an under-active thyroid needing lifelong tablets), and less often the pituitary (hypophysitis) or adrenal glands, which can be life-threatening if missed.
Burning pain, redness and heat in the hands or feet, brought on by warmth. In polycythaemia vera and essential thrombocythaemia it comes from platelets clumping in tiny vessels and often disappears with low-dose aspirin.
Inflammation of the bowel caused by immunotherapy releasing the immune system against the gut lining, producing diarrhoea that can be severe. It is the commonest serious side effect of CTLA-4 antibodies and is treated with steroids and, if needed, infliximab.
See all on the product pages:AspirinAtezolizumabDostarlimabFOLFOX (5-FU, leucovorin, oxaliplatin)IpilimumabNivolumabPembrolizumab·Printable cards in the navigator
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