Impact of mucinous histology on the efficacy of neoadjuvant immunotherapy in localized mismatch repair-deficient colorectal cancer

BACKGROUND: The response of mucinous colorectal cancer (CRC) to immunotherapy remains unclear. This study aimed to evaluate the efficacy of neoadjuvant immunotherapy in localized mucinous mismatch repair-deficient (dMMR) CRC. METHODS: This retrospective study included patients with localized dMMR CRC who underwent neoadjuvant immunotherapy. Patients were classified into adenocarcinoma (AC) and mucinous carcinoma (MC) groups. Clinicopathological and treatment data were recorded. Logistic regression analysis was performed to identify predictors of complete response (CR). RESULTS: A total of 220 patients were included, of whom 25(11.4%) had MC. Patients with MC had significantly lower clinical complete response (cCR) rates (20.0% vs. 44.1%, P = 0.021) and objective response rates (64.0% vs. 92.8%, P < 0.001) than those with AC. In addition, patients with MC showed lower pCR, poorer tumor regression, and more aggressive pathology. In MC patients, combination therapy was associated with greater tumor regression than anti-PD-1 monotherapy (83.3% vs. 28.6%, P = 0.045). Among patients who underwent surgery, the 2-year disease-free survival rate was 94.1% in the MC group and 100% in the AC group. Multivariate analysis identified MC histology as an independent negative predictor of CR (Odds ratio [OR] = 0.22, 95% confidence interval [CI]: 0.09-0.56; P = 0.002), whereas a treatment duration ≥ 3 months significantly increased the probability of CR in all patients. During neoadjuvant treatment, severe (grade 3-4) immune-related adverse events (irAEs) occurred in 15 patients (7.7%, 15/195) in the AC group and 1 patient (4.0%, 1/25) in the MC group. CONCLUSION: Patients with localized MC dMMR CRC tend to have inferior responses to immunotherapy compared with patients with AC. Optimizing treatment duration or modifying treatment regimens may improve therapeutic outcomes in this subgroup.