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Microsatellite-instable (MSI) tumours constitute one-fifth of colorectal cancers (CRCs). However, the MSI CRCs display substantial tumour microenvironment (TME) heterogeneity and variable responses to immunotherapy, necessitating a refined classification to guide personalized therapy. In this study, we analysed whole-genome and transcriptome sequences from 223 MSI CRC patients from a large prospective longitudinal cancer study in Sweden (Nunes L, Li F, Wu M, et al. Prognostic genome and transcriptome signatures in colorectal cancers. Nature. 2024;633(8028):137-146) and identified three molecular subclasses with distinct TME and genetic features: class 1a (immune-excluded), characterized by prominent stromal activation, transforming growth factor-β signalling, and low tumour neoantigen burdens (TNB); class 1b (immune-infiltrated), marked by intact neoantigen presentation and strong antitumour immunity; and class 2 (immune-cold), exhibiting epithelial features, high tumour mutation burden (TMB) and TNB, chromosomal instability, active metabolism, and a lack of immune activation. We further uncovered a correlation between mutL homolog 1 (MLH1) hypermethylation and the immune-cold phenotype in class 2, where anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) combination immunotherapy demonstrated significantly improved efficacy compared with anti-PD-1 monotherapy. Finally, the molecular features of these subclasses were validated in external MSI CRC cohorts and in MSI tumours from other cancers. Our findings offer a comprehensive understanding of the molecular landscape of MSI CRC, unveiling potential molecular mechanisms underlying different tumour-immune phenotypes and laying the foundation for future development of tailored treatment strategies.